UA107451C2 - Pyridyloxyindoles - inhibitors of vegf-r2 and their use for the treatment of disease - Google Patents

Abstract

The invention relates to novel organic compounds of formula (III), and their use in the treatment of the animal or human body, to pharmaceutical compositions comprising a compound of formula III and to the use of a compound of formula III for the preparation of pharmaceutical compositions for use in the treatment of protein kinase dependent diseases, especially of proliferative diseases, such as in the treatment of tumour diseases and ocular neovascular diseases.

Description

The present invention relates to bicyclic heterocyclic compounds of the formula I, substituted in both rings, and to the use of the compound of the formula I for the preparation of pharmaceutical compositions intended for use in the treatment of protein kinase-dependent diseases, mainly proliferative diseases, such as especially tumor diseases and eye revascularization diseases.

Protein kinases (PCs) are enzymes that catalyze the phosphorylation of specific serine, threonine, or tyrosine residues in cellular proteins. These post-translational modifications of substrate proteins act as molecular switches that regulate cell proliferation, activation and/or differentiation. Aberrant or excess wild-type or mutated PC activity has been observed in many pathological conditions, including benign and malignant proliferative disorders. In many cases, it has been possible to treat diseases such as proliferative disorders with PC inhibitors.

Due to the large number of protein kinases and the multitude of proliferative and other PC-related diseases, there is a constant need for compounds that are useful as PC inhibitors and therefore useful in the treatment of these PC-related diseases.

According to the invention, it was established that the compounds of formula I inhibit a number of protein kinases. Compounds of formula I, described in more detail below, in particular, inhibit one or more of the following protein kinases: ErpB4, c-ABI, All-ABI, c-Kai, Kai kinase, preferably such as B-Kai, a photo-oncogene that rearranges during transfection (KET), platelet-derived growth factor receptors (ROSBE-K5) and most preferably vascular endothelial growth factor receptors (MESB-K5), such as especially MESE-K2. The compound of formula I! also inhibits mutants of these kinases. As a result of such activity of compounds of the formula | can be used to treat diseases, especially associated with aberrant or excessive activity of these types of kinases, preferably the specified kinases.

This invention relates to compounds of the formula Y,

In o /

Vo Z ry Ne Ago

M

M y 71 X Th Vu ra ra | r and:

Vio 72 XX

Az

In" a or their salts, in which

B: denotes hydrogen or C.1-Cv-alkyl;

B2 denotes hydrogen or C1-C8-alkyl;

Bz denotes hydrogen or C1-C8-alkyl;

Va denotes hydrogen or C1-C8-alkyl; or

B2 and Ka, taken in combination, form a bond;

B5 denotes hydrogen, Ci-Cv-alkyl or halogen;

Ve are 0, 1 or 2 residues, in each case independently selected from the group consisting of halogen or Ci-Cv-alkyl;

IN? denotes hydrogen or C.1-Cv-alkyl;

X stands for O or 5; 71 and 7" are independently selected from the group consisting of M and SKv;

Bv and Co are independently selected from the group consisting of hydrogen and C:-C6-alkyl;

Be selected from the group consisting of (SC1Vig)aMMA:zAcha, (SVy1Vig)heterocyclyl, (SC11Ai12)OOV'v5, (SVyVig)oC(OEViz) and (SCVyg)po(O)tVy7; or

Bv and Co", taken in combination, together with the atoms to which they are attached, form a saturated 4- to 7-membered heterocyclic ring containing 1 or 2 ring heteroatoms selected from the group consisting of

M, O, or 5, and this heterocyclic ring is substituted with 0, 1, or 2 residues independently selected from the group consisting of an oxo group, a C:-Cv-alkyl, a C1-Cv-haloalkyl, a C1-C6-alkyl group, /C1 -Cv- haloalkoxy group, halogen, hydroxy group, amino group, hydroxy-C1-Cv-alkyl, amino-Ci-Cv-alkyl, mono- and di-Ci-Cv-alkylamino-Ci-Cv-alkyl, C3-C7-cycloalkyl- C-C"-alkyl, heterocycle-Ci-C-alkyl, C1-Cv-alkanoyl, mono- and di-C1-Cv-alkylamino group, aminocarbonyl, mono- and di-C1-Cv-alkylaminocarbonyl, mono- and /di -Ci-C"-alkylamino-C--C--alkanoyl, Ci-Ci-alkylsulfonyl,

aminosulfonyl and mono- and di-C1-C6-alkylaminosulfonyl;

Ag2g is selected from the group consisting of phenyl, naphthyl, monocyclic or bicyclic heteroaryl and bicyclic or tricyclic heterocyclyl, where each heteroaryl or heterocyclyl residue contains 1, 2, 3 or 4 ring heteroatoms selected from the group consisting of M, O or 5, and wherein the phenyl, naphthyl, heteroaryl or heterocyclyl group is unsubstituted or substituted with 1, 2 or C groups independently selected from the group consisting of C1-C8-alkyl, C1-C8-haloalkyl, hydroxy-C1-C8-alkyl, C1- Cl-aluoxy group, Cl-Cv-halogenalkoxy group, halogen, hydroxy group, amino group, amino-C1-Cv-alkyl, mono- and di-Ci-Cv-alkylamino-Ci-Cv-alkyl, mono- and di-C1-Cv- alkylamino group, СО2гС-1-Св-alkyl, phenyl-Со-С4-alkyl, С3-С7-cycloalkyl-Со-С4-alkyl, spirocyclic С3-С7-cycloalkyl, aminosulfonyl and mono- and di-Си-Св-alkylaminosulfonyl; t is equal to 0, 1 or 2; n is equal to 0, 1, 2 or 3;

E is absent or denotes O or ME in;

Wit, Wiig and Kiv are the same or different and in each case independently selected from the group consisting of hydrogen and C1-C4 alkyl; and

Wiz, Ba, Bi, Viv and Ki7 are each independently selected from the group consisting of hydrogen, C1-C8-alkyl, C1-C8-alkanoyl, C3-C8-cycloalkyl, phenyl and heterocyclyl, each of which is substituted with 0, 1 or 2 residues independently selected from the group consisting of C1-C4-alkyl, C1-C4-alkyl, halogen, hydroxy, amino, and mono- and di-C1-C6-alkylamino.

The present invention also relates to a method of treating a kinase-dependent and/or proliferative disease, comprising administering a compound of formula I to a warm-blooded animal, preferably a human, and to the use of a compound of formula I, preferably for the treatment of a kinase-dependent disease or disorder. The present invention also relates to pharmaceutical preparations comprising a compound of formula I, preferably for the treatment of a kinase-dependent disease or disorder, to a method for the preparation of a compound of formula I and new starting substances and intermediates for their preparation. This invention also relates to the use of the compound of formula I! for the preparation of a pharmaceutical preparation intended for the treatment of a kinase-dependent disease.

General terms used above and below in the present invention, in the context of this disclosure, unless otherwise indicated, preferably have the following meanings (where preferred embodiments can be determined by replacing one or more and up to all general expressions or notations with ( a) a more specific or better (better) definition given in this invention):

Some compounds of formula I proposed in this invention are compounds of formula I: 8; about /

M

Ve Ago

M and M

And "

J

M Xh

Az

Not Her or their salts, in which

B: denotes hydrogen or C.1-Cv-alkyl;

Bz denotes hydrogen or C1-C8-alkyl;

B5 denotes hydrogen or halogen;

IN? denotes hydrogen or C.1-Cv-alkyl;

X stands for O or 5;

Vzv is selected from the group consisting of hydrogen and C:-Cα-alkyl;

Be selected from the group consisting of (SC1Vig)aMMA:zAcha, (SVy1Vig)heterocyclyl, (SC11Ai12)OOV'v5, (SVyVig)oC(OEViz) and (SCVyg)po(O)tVy7; or

Bv and K", taken in combination, with the atoms to which they are attached, form a saturated 4- to 7-membered heterocyclic ring containing 1 or 2 ring heteroatoms selected from the group consisting of M, O or 5, and this heterocyclic ring is substituted with 0, 1 or 2 residues independently selected from the group consisting of C1-C8-alkyl, C1-C8-haloalkyl, halogen, hydroxy-C1-C8-alkyl, amino-C1-C8 -alkyl, C3-C7-

cycloalkyl-C1-C4-alkyl, heterocycle-C1-Ca-alkyl, Ci-Cv-alkanoyl, mono- and di-Ci-Cv-alkylaminocarbonyl, mono- and di-C1-Ca-alkylamino-C1-C"-alkanoyl , Ci-Cv-Alkoxycarbonyl and Ci-Cv-Alkylsulfonyl;

Agg2 represents a phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, wherein each heteroaryl contains 1, 2, or 3 ring heteroatoms selected from the group consisting of M, O, or 5, and wherein the phenyl, naphthyl, or heteroaryl group is unsubstituted or substituted with 1, 2 or C groups independently selected from the group consisting of C1-C8-alkyl, C1-C8-haloalkyl, halogen, hydroxy, SOOC, phenyl and C3-C-cycloalkyl; t is equal to 0, 1 or 2; n is equal to 0, 1, 2 or 3;

E denotes O or ME in;

Wit, Bii2 and Kiv are the same or different and in each case independently selected from the group consisting of hydrogen and C1-C4 alkyl; and

Wiz, Ba, Bi, Viv, and Ki7 are each independently selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, phenyl, and heterocyclyl, each of which is substituted with 0, 1, or 2 independently selected residues from the group including a hydroxy group, an amino group, and a mono- and di-C1-Cv-alkylamino group.

Some other compounds of formula I proposed in this invention are compounds of the formula

PI: 8; about /

M

Ve M Ago

M chu yt v

M Xh

Az

No. PI or their salts, in which

B: denotes hydrogen or C.1-Cv-alkyl;

Bz denotes hydrogen or Ci-Cv-alkyl;

B5 denotes hydrogen or halogen;

IN? denotes hydrogen or C.1-Cv-alkyl;

X stands for O or 5;

Vzv is selected from the group consisting of hydrogen and C:-Cα-alkyl;

Be selected from the group consisting of (SC1Vig)aMMA:zAcha, (SVy1Vig)heterocyclyl, (SC11Ai12)OOV'v5, (SVyVig)oC(OEViz) and (SCVyg)po(O)tVy7; or

Bv and Co", taken in combination, together with the atoms to which they are attached, form a saturated 4- to 7-membered heterocyclic ring containing 1 or 2 ring heteroatoms selected from the group consisting of

M, O or 5, and this heterocyclic ring is substituted with 0, 1 or 2 residues independently selected from the group consisting of C:-Cv-alkyl, Ci-Cv-haloalkyl, halogen, hydroxy-C1-Cv-alkyl, amino- С:-Св-alkyl, Сз-

C-cycloalkyl-Ci-Ca-alkyl, heterocycle-C1-C4-alkyl, Ci-Cv-alkanoyl, mono- and di-C1-Cv- alkylaminocarbonyl, mono- and di-C1-C4-alkylamino-Ci-C4- -alkanoyl, C1-C8-alkoxycarbonyl and C1-C8-alkylsulfonyl;

Agg2 denotes phenyl, naphthyl, 5- or b-membered monocyclic heteroaryl, wherein each heteroaryl contains 1, 2, or 3 ring heteroatoms selected from the group consisting of M, O, or 5, and wherein the phenyl, naphthyl, or heteroaryl group is unsubstituted or substituted with 1, 2 or C groups independently selected from the group consisting of C1-C8-alkyl, C1-C8-haloalkyl, halogen, hydroxy, SOOC, phenyl and C3-C-cycloalkyl; t is equal to 0, 1 or 2; n is equal to 0, 1, 2 or 3;

E denotes O or ME in;

Wit, Wiig and Kiv are the same or different and in each case independently selected from the group consisting of hydrogen and C1-C4 alkyl; and

Wiz, Ba, Bi, Viv, and Ki7 are each independently selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, phenyl, and heterocyclyl, each of which is substituted with 0, 1, or 2 independently selected residues from the group including a hydroxy group, an amino group and mono- and di-C1-Cv-

alkylamino group.

In some embodiments, the compounds of formulas I, II and/or I include such compounds in which K. and

Vz denotes hydrogen. In some other compounds of formulas I, II and/or I, K: represents hydrogen or C-C4 alkyl (e.g., methyl or ethyl), Kz represents hydrogen, and either (1) E2 and Ka represent hydrogen, or (2)

B2 and Ka, taken in combination, form a bond.

In some embodiments, K5 is selected from the group consisting of hydrogen, methyl, methoxy, fluorine, or chlorine. In some other embodiments, K5 is selected from the group consisting of hydrogen or fluorine. In some compounds of formula I, K: denotes methyl or ethyl and K5 denotes fluorine.

In some other embodiments, Ke is absent.

In some compounds of formulas I, P or I, KE; represents hydrogen or methyl. In other embodiments, K7 is hydrogen.

In other embodiments, X represents oxygen.

Certain compounds of formula I, II and/or I include those in which K: is hydrogen or C1-C4 alkyl (eg, methyl or ethyl), K3 is hydrogen, K5 is hydrogen or fluorine, Not present, X is oxygen, and or (1) E2 and Ka represent hydrogen, or (2) E» and Pa, taken in combination, form a bond.

In some embodiments, Kav represents hydrogen. In other embodiments, K:io represents hydrogen. In other embodiments, Kz and K:o represent hydrogen.

In some embodiments, K:io represents hydrogen and Kv and Co" taken in combination form a saturated 5- or b-membered heterocyclic ring containing 1 ring nitrogen atom, and this heterocyclic ring is substituted with 0, 1, or 2 residues, regardless of selected from the group including C1-

Ca-alkyl, Ci-C.-haloalkyl, hydroxy-C1-C4-alkyl, amino-C1i-C4--alkyl, heterocycle-Ci-Ca-alkyl, C1-C4- alkanoyl, mono- and di-Ci-C4 --alkylaminocarbonyl, mono- and di-Ci-C4-alkylamino-C1-C--alkanoyl, mono- and di-C1-C"-alkylaminocarbonyl-C1-C-alkyl, aminocarbonyl-C1-C"-alkyl, Si -С4--Alkoxycarbonyl and С1-Са4-Alkylsulfonyl.

Some compounds of formula I, I or I in which Kv and Ke form a ring include those in which the fragment:

Ve in t | and ra sia y

Vo M Xx is selected from among the residues of the formula:

Wow

Viva | Aha

Av M No,

Noza ai H2z sh g -

M x and their salts, in which p is 0 or 1;

Viv, Viva, Ngo, H2i, Nota, H2z, and K2za, independently selected from the group consisting of hydrogen, oxo, hydroxy, C1-C6-alkyl, C1-C4-haloalkyl, hydroxy-C1-C6-alkyl, HOS( О)СН»г, МНгС(О)СН», mono- and di-С1-Са-alkyl-МНнМес(О)СН»г, Си-С4-alkanoyl, mono- and di-С1и-С4-alkyl-С -C--alkanoyl, /C1-C4- sulfonyl, or K'" and Kwa, taken in combination, or Kg and Koza, taken in combination, or Kgz and Kgza, taken in combination, form 3- - 7-h- lazy spirocyclic ring. In some other compounds K'iva, Va, Vgz, and

Hgza represents hydrogen, 2 of the variables Co, Hgo or Koch represent hydrogen and the other is selected from the group consisting of hydrogen, methyl, ethyl or hydroxyethyl.

Some variants of implementation refer to compounds of formula I or I, described by formula IM:

Ao

IN;

A M Ve o / x ) Ago

M

M r sh | Y V,

M Xh

Az

Not IM and their salts, in which p is 0 or 1;

W, W, and R are independently selected from the group consisting of hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl,

МНС(О)СН»: and МНМес(О сн»).

Certain compounds of formula IM include compounds in which 2 of the variables Ki, B, or Ki are hydrogen and the other is selected from the group consisting of hydrogen, methyl, ethyl, or hydroxyethyl. Certain other compounds of formula IM include those in which p is 0, K 1 and K 2 are hydrogen, and K 20 is selected from the group consisting of hydrogen, methyl and ethyl.

Some variants of implementation refer to compounds of formula I or II, described by formula Y:

AND; about /

Well

Oh, and M

M sh | And you

M Xh

Az

В В and their salts, in which

B» is selected from the group consisting of CH2MA, CH2OB:5, CH2C(O)ENi3 and CH»Z(O)2ENI7; or

E is absent or denotes O or ME in;

Viv represents hydrogen, methyl or ethyl; and

Wiz, Ba, Bi, Viv and Ki7 are each independently selected from the group consisting of hydrogen, C1-C4-alkyl and hydroxy-C:-C6-alkyl.

In some compounds of formula 1, ЖІІ, Ш or МКe is selected from the group consisting of (CHheg)MNV z, (SVVyg)vheterocyclyl, (SE ch1Vy12)OOV5, (CHg)p5(O) tVy? and (CHg)a5(O)tM(B c) 2; n is equal to 1 or 2;

Wiz denotes hydrogen, C1-C6-alkyl, hydroxy-C1-C-alkyl, or C3-C6-cycloalkyl;

Vi" denotes hydrogen or Ci-Ca-alkyl;

you denotes C--Cα-alkyl;

V is in each case independently selected from the group consisting of hydrogen, methyl, or ethyl.

In some other compounds of formula I or II or their salts, in which

B: represents hydrogen, methyl or ethyl;

Az represents hydrogen;

B5 denotes hydrogen, fluorine or chlorine;

X stands for O or 5;

Vzv is selected from the group consisting of hydrogen and C:-Cα-alkyl;

Be selected from the group consisting of СНеMM:зНАч14, СНе-heterocyclyl, СН2ОН:5, СНаС(О)ЕВИ!z and

SN»B(O)2ENI7; or

Vv and Ko", taken in combination, form a saturated 4- to 7-membered heterocyclic ring containing one nitrogen atom, and this heterocyclic ring is substituted by 0, 1 or 2 residues, independently selected from the group including C.: -Cv-alkyl, Ci-Cv-haloalkyl, halogen, Ci-Cv-alkanoyl and Ci-Cv-alkylsulfonyl;

Ag" denotes a phenyl, 5-membered monocyclic heteroaryl, wherein each heteroaryl contains one ring nitrogen atom and 0 or 1 additional ring heteroatom selected from the group consisting of M, O, or 5, and wherein the phenyl or heteroaryl group is unsubstituted or substituted with 1, 2 or C groups independently selected from the group consisting of C-Cv-alkyl, C-Cv-haloalkyl, halogen, hydroxy group,

СО Ж, phenyl and C3-C7-cycloalkyl; t is equal to 0, 1 or 2; n is equal to 0, 1, 2 or 3;

E denotes O or ME in;

Viv is selected from the group consisting of hydrogen and C1-C4-alkyl; and

Wiz, Ba, Bi, Viv, and Ki7 are each independently selected from the group consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, phenyl, and heterocyclyl, each of which is substituted with 0, 1, or 2 independently selected residues from the group including a hydroxy group, an amino group, and a mono- and di-C1-Cv-alkylamino group.

In some compounds of formula I, II, MP, IM or M or salts thereof, Ag represents phenyl, which is unsubstituted or substituted by 1 or 2 groups independently selected from the group consisting of halogen, C1-C6-alkyl, C1-

C.4-Alkoxy group, C1i-C4-halogenoalkyl and C-C4-halogenoloxy group. In other compounds of formulas I, PI, M,

IM or M or their salts Ag denotes a 5-membered heteroaryl containing 1 ring nitrogen atom and 0 or 1 additional ring heteroatom selected from the group consisting of M and O, and where said heteroaryl group is unsubstituted or substituted by 1 or 2 groups independently selected from the group consisting of C-C-alkyl, C1-C-haloalkyl, C-C4-alukoxy group, C-C-halogenoxy group, halogen, amino group, amino-Ci--Ca-alkyl, mono- and di-Si-C--alkylamino-Si-Ca-alkyl, mono- and di-C1-C4- alkylamino group, hydroxy group, Сог2Си1-Са-alkyl, phenyl-Со-Са-alkyl, C3-Св-cycloalkyl -Co-C2-alkyl, aminosulfonyl and mono- and di-C1-C4-alkylaminosulfonyl. In some other compounds of formulas I, PI, M,

M or M or their Ag salts: denotes a bicyclic heterocycle containing a ring nitrogen atom and 0 or 1 additional ring heteroatom selected from the group consisting of M and O, which is saturated, partially saturated or partially aromatic (eg, heteroaryl or phenyl a ring fused to a heterocyclic or carbocyclic ring such that the bicyclic heterocycle contains at least one ring heteroatom in at least one ring) and wherein the bicyclic heterocycle is unsubstituted or substituted with 1 or 2 groups independently selected from the group consisting of C-C4- alkyl, C-C4-haloalkyl, C1-C4-alkoxy group, C-C4-halogenoxy group, halogen, amino group, amino-Ci--Ca-alkyl, mono- and di-Ci-C--alkylamino-Ci-Ca -alkyl, mono- and di-C1-C4- alkylamino group, hydroxy group, COg2Ci1-Ca-alkyl, phenyl-Co-Ca-alkyl, C3-Cv-cycloalkyl-Co-C2-alkyl, aminosulfonyl and mono- and di-C1 -C4-alkylaminosulfonyl. In some compounds in which Ag is a 5-membered heteroaryl or bicyclic heterocycle, Ag is unsubstituted or substituted by C1-C6-alkyl or hydroxy-C1-C6-alkyl.

In some compounds of formulas I, II, 1, IM or M or their salts, Ag" denotes the group of the formula: m-4

X d--" I'm in which one

ABg2 is selected from the group consisting of C1i-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-Ca-alkyl, Ci-

C4-haloalkyl, hydroxy-Ci-Ca-alkyl, phenyl, 5- and b--len heterocyclyl; and 7 denotes О, МН or

M(C1-C4-alkyl). In some compounds, E2g2 is selected from the group consisting of C1-C4-alkyl, C3-C6-cycloalkyl, 1-methyl-C3-C6-cycloalkyl, C1-C0-haloalkyl and hydroxy-C1-C4-alkyl; and 7 denotes О or МН. In other compounds, Kgg is selected from the group consisting of isopropyl, tert-butyl, cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 1-trifluoromethylcyclopropyl, 1-ethylcyclopropyl, 1-methylcyclobutyl, 1-methylcyclobutyl, hydroxy-tert-butyl and trifluoromethyl; and 7 is O. Some compounds in which 7 is M can exist as one or both 1H- or 2H-tautomers of pyrazole, for example

Zhd fe u i i 2n1n

Some compounds of the formula | include exemplified compounds obtained in the present invention.

Certain compounds of formula I include compounds selected from the group consisting of:

(3-trifluoromethylphenyl)-amide (5-(7-ethyl-5,6,7,8-tetrahydropyridoyl)3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid; 5-(b-methylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (4-fluoro-3-trifluoromethylphenyl)-amide; (4-fluoro-3-trifluoromethylphenyl)-amide b-tetrazol-2-ylmethylpyrimidin-4-yloxy)-indole-1-carboxylic acid; 5-(6-cyclopropylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (4-fluoro-3-trifluoromethylphenyl)-amide; 5-(5,6,7,8-tetrahydropyrido[3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide;

M-(4-fluoro-3-"(trifluoromethyl)phenyl)-5-(6-(methylsulfonylmethyl)pyrimidin-4-yloxy)-1H-indole-1-carboxamide;

M-(4-methoxy-3-(trifluoromethyl)phenyl)-5-(6-(methylamino)methyl)pyrimidin-4-yloxy)-1H-indole-1-carboxamide; 5-(7-methanesulfonyl-5,6b,7,8-tetrahydropyrido|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide; 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (b-tert-butylisoxazol-3-yl)-amide; (3-trifluoromethylphenyl)-amide 5-16-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy|-indole-1-carboxylic acid; 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl phenyl)-amide; 5-(5,6,7,8-tetrahydropyridoyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (4-fluoro-3-trifluoromethylphenyl)-amide; 5-(5,6,7,8-tetrahydropyrido|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (b-tert-butylisoxazol-3-yl)-amide; (3-trifluoromethylphenyl)-amide (-)-(5)-5-(6b-methyl-5,6,7,8-tetrahydropyrido|3,4-4|pyrimidin-4-yloxy)-indole-1-carbon acids; (3-trifluoromethylphenyl)-amide (g)-(H)-5-(b-methyl-5,6,7,8-tetrahydropyridoyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid; 4-fluoro-(3-trifluoromethylphenyl)-amide 5-(5,6,7,8-tetrahydropyridoyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid; 5-(b-methylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (5-tert-butyl-2H-pyrazol-3-yl)y-amide; 5-(6,7-dihydro-5H-pyrroloyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (2-fluoro-3-trifluoromethylphenyl)-amide; (5-Cyclopropylisoxazol-3-yl)-amide 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid; (5-isobutylisoxazol-3-yl)-amide 5-(6,7-dihydro-5H-pyrrolyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid;

5-(1-methylcyclopropyl)-isoxazol-3-yl|-amide 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid; (5-tert-butyl-2H-pyrazol-3-yl)-amide 5-(5,6,7,8-tetrahydropyridoyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid; 5-(6-methyl-b,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide; 5-(5,6,7,8-tetrahydropyridoyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-fluoro-5-trifluoromethylphenyl)-amide; 6,7-dihydro-5H-pyrrolo!|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-tert-butylisoxazol-5-yl)-amide; (5-tert-butylisoxazol-3-yl)-amide (-)-5-methyl-b,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid ; (5-tert-butylisoxazol-3-yl)-amide (g)-5-methyl-b,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid ; 4-fluoro-2-methyl-5-(6-(methylamino)methyl)pyrimidin-4-yloxy)-M-(3(trifluoromethyl)-phenyl)-1H-indole-1-carboxamide;

5-(1-methylcyclopropyl)-2H-pyrazol-3-yl|-amide 5-(5,6,7,8-tetrahydropyridoyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid; 4-fluoro-5-(6-methylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (b-trifluoromethyl-1H-pyrazol-3-yl)-amide; (b-tert-butylisoxazol-3-yl)-amide (9y-5-((5)-6-methyl-5,6,7,8-tetrahydro-pyridoyl3,4-4|pyrimidin-4-yloxy)- indole-1-carboxylic acid;

(b-tert-butylisoxazol-3-yl)-amide (-)-5-((H8)-6-methyl-5,6,7,8-tetrahydro-pyridoyl3,4-4|pyrimidin-4-yloxy) -indole-1-carboxylic acid;

5-(1-methylcyclopropyl)-2H-pyrazol-3-yl|-amide 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid ; 5-(2-(2-morpholinoethyl)pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide; (5-isopropylisoxazol-3-yl)-amide 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid; 5-(5,6,7,8-tetrahydropyrido|4,3-4|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide; (3-trifluoromethylphenyl)-amide 5-I6-(18, 45)-5-acetyl-2,5-diazabicyclo|2.2.1|hept-2-ylmethyl)-pyrimidin-4-yloxy|-indole-1-carbon acids; 5-(6-methanesulfonylmethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (2-fluoro-3-trifluoromethylphenyl)-amide; (3-trifluoromethylphenyl)-amide 5-(2-(5-oxo-4,5-dihydro-(1,3,4|oxadiazol-2-yl)-pyridin-4-yloxy)|-indole-1-carboxylic acid acid; (3-trifluoromethylphenyl)-amide 5-I(7-(3-diethylaminopropionyl)-5,6,7,8-tetrahydropyrido3,4-a|pyrimidin-4-yloxy|-indole-1-carboxylic acid; ( 3-trifluoromethylphenyl)-amide 5-(2-cyclopropylcarbamoylpyridin-4-yloxy)-indole-1-carboxylic acid; (4-fluoro-3-trifluoromethylphenyl)-amide 6-(5-methyltetrazol-2-ylmethyl)-pyrimidine- 4-yloxy|-indole-1-carboxylic acid;

15-(1-methylcyclopropyl)-2H-pyrazol-3-yl|-amide 5-((5)-6-methyl-5,6,7,8-tetrahydropyridoi3,4-a|pyrimidin-4-yloxy)- indole-1-carboxylic acid;

15-(1-methylcyclopropyl)-2H-pyrazol-3-yl|-amide 5-(H)-6-methyl-5,6,7,8-tetrahydropyrido3,4-a|pyrimidin-4-yloxy)-indole -1-carboxylic acid;

15-(4-fluorophenyl)-isoxazol-3-yl|-amide of 5-(6,7-dihydro-5H-pyrroloyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid; 5-N6-(4-methanesulfonylaminopiperidin-1-ylmethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide; (3-trifluoromethylphenyl)-amide 5-N7-(2-hydroxyethyl)-5,6,7,8-tetrahydropyridoyl3,4-4|pyrimidin-4-yloxy|-indole-1-carboxylic acid; 5-(2-methylcarbamoylpyridin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide;

I5-(2-hydroxy-1,1-dimethylethyl)-2H-pyrazol-3-yl|I-amide 5-(5,6,7,8-tetrahydropyridoyl3,4-d|pyrimidin-4-yloxy)-indole -1-carboxylic acid; 5-(5,6,7,8-tetrahydropyrido|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (b-trifluoromethylpyridin-3-yl)-amide; 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (1-methyl-1H-indol-4-yl)-amide; 5-(6-morpholin-4-ylmethylpyrimidin-4-yloxy)-2,3-dihydroindole-1-carboxylic acid (3-trifluoromethylphenyl)-amide hydrochloride; 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-2-methylindole-1-carboxylic acid (5-tert-butylisoxazol-3-yl)-amide; 5-(2-Hydroxymethylpyridin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide; 5-(6-isobutylpyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide; (5-phenyl-2H-pyrazol-3-yl)-amide 5-(5,6,7,8-tetrahydropyridoyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid; 2-methyl-(3-trifluoromethylphenyl)-amide of 5-(5,6,7,8-tetrahydropyrido|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid; 4-fluoro-I5-(1-methylcyclopropyl)-2H-pyrazol-3-yl|I-amide 5-(5)-6-methyl-5,6,7,8-tetrahydropyridoi|3,4-a|pyrimidine -4-yloxy)-indole-1-carboxylic acid; 4-Fluoro-I5-(1-methylcyclopropyl)-2H-pyrazol-3-yl|I-amide 5-(HA)-6-methyl-5,6,7,8-tetrahydropyridoyl3,4-a|pyrimidine-4 -yloxy)-indole-1-carboxylic acid; 5-(b-pyrrolidin-1-ylmethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide; 5-(2-cyclopropylaminomethylpyridin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide; (5-cyclopropylisoxazol-3-yl)-amide (-)-5-((5)-7-acetyl-b-methyl-5,6,7,8-tetrahydropyridoi|3,4- a|pyrimidine-4- yloxy)-indole-1-carboxylic acid; 4-fluoro-5-(2-methanesulfonylmethylpyrimidin-4-yloxy)-2-methylindole-1-carboxylic acid (3-trifluoromethylphenyl)-amide; 5-(6-methylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)-amide; and their tautomers and/or their pharmaceutically acceptable salts.

In a preferred embodiment, the present invention relates to a compound selected from the group consisting of (3-trifluoromethylphenyl)-amide /5-(7-ethyl-5,6,7,8-tetrahydropyridoyl)3,4-4|pyrimidin-4-yloxy )-indole-1-carboxylic acid; 5-(b-methylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (4-fluoro-3-trifluoromethylphenyl)-amide; (4-fluoro-3-trifluoromethylphenyl)-amide b-tetrazol-2-ylmethylpyrimidin-4-yloxy)-indole-1-carboxylic acid; 5-(5,6,7,8-tetrahydropyrido|3,4-4|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide;

M-(4-fluoro-3-"(trifluoromethyl)phenyl)-5-(6-(methylsulfonylmethyl)pyrimidin-4-yloxy)-1H-indole-1-carboxamide; 5-(7-methanesulfonyl-5,6b,7,8-tetrahydropyrido|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide; 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (b-tert-butylisoxazol-3-yl)-amide; (3-trifluoromethylphenyl)-amide 5-16-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy|-indole-1-carboxylic acid; 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl phenyl)-amide; 5-(5,6,7,8-tetrahydropyrido|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (b-tert-butylisoxazol-3-yl)-amide; (3-trifluoromethylphenyl)-amide (-)-(5)-5-(6b-methyl-5,6,7,8-tetrahydropyrido|3,4-4|pyrimidin-4-yloxy)-indole-1-carbon acids; (3-trifluoromethylphenyl)-amide (g)-(H)-5-(b-methyl-5,6,7,8-tetrahydropyridoyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid; 4-fluoro-(3-trifluoromethylphenyl)-amide 5-(5,6,7,8-tetrahydropyrido[3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid; 5-(6,7-dihydro-5H-pyrroloyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (2-fluoro-3-trifluoromethylphenyl)-amide; (5-Cyclopropylisoxazol-3-yl)-amide 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid;

5-(1-methylcyclopropyl)-isoxazol-3-yl|-amide 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid;

5-(1-methylcyclopropyl)-2H-pyrazol-3-yl|-amide 5-(5,6,7,8-tetrahydropyridoyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid; (b-tert-butylisoxazol-3-yl)-amide (9y-5-((5)-6-methyl-5,6,7,8-tetrahydro-pyridoyl3,4-4|pyrimidin-4-yloxy)- Indole-1-carboxylic acid; 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (5-isopropylisoxazol-3-yl)-amide (3-trifluoromethylphenyl)-amide 5-I(7-(3-diethylaminopropionyl)-5,6,7,8-tetrahydropyrido3,4-a|pyrimidin-4-yloxy|-indole-1-carboxylic acid;

15-(1-methylcyclopropyl)-2H-pyrazol-3-yl|-amide 5-((5)-6-methyl-5,6,7,8-tetrahydropyridoi3,4-a|pyrimidin-4-yloxy)- indole-1-carboxylic acid;

15-(1-methylcyclopropyl)-2H-pyrazol-3-yl|-amide 5-(H)-6-methyl-5,6,7,8-tetrahydropyrido3,4-a|pyrimidin-4-yloxy)-indole -1-carboxylic acid; (5-cyclopropylisoxazol-3-yl)-amide 5-((5)-6-methyl-5,6,7,8-tetrahydropyrido|3,4-4|pyrimidin-4-yloxy)-indole-1-carbon acids; 5-(b-methylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (5-isopropyl-1H-pyrazol-3-yl)-amide; 5-(b-methylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (5-cyclopropyl-1H-pyrazol-3-yl)-amide; 5-(6-methylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)-amide;

15-(1-methylcyclopropyl)-isoxazol-3-yl|-amide of 5-(6b6-methylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid;

15-(1-trifluoromethylcyclopropyl)-isoxazol-3-yl|-amide 5-(5)-7-acetyl-b6-methyl-5,6,7,8-tetrahydropyridoyi3,4-4|pyrimidin-4-yloxy) -indole-1-carboxylic acid;

15-(1-trifluoromethylcyclopropyl)-isoxazol-3-yl|-amide 5-(5)-6-methyl-7-(3-methylbutyryl)-5,6,7,8-tetrahydropyridoyi3,4-4|pyrimidine- 4-yloxy|-indole-1-carboxylic acid;

15-(1-trifluoromethylcyclopropyl)-isoxazol-3-yl|-amide 5-(5)-7-cyclopropylmethyl-b-methyl-5,6,7,8-

tetrahydropyridoyi3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid;

15-(1-trifluoromethylcyclopropyl)-isoxazol-3-yl|-amide 5-((5)-7-ethyl-b-methyl-5,6,7,8-tetrahydropyridoyi3,4-4|pyrimidin-4-yloxy )-indole-1-carboxylic acid; (5-cyclopropylisoxazol-3-yl)-amide 5-((5)-7-cyclopropanecarbonyl-b-methyl-5,6,7,8-tetrahydropyridoyl3,4-4|pyrimidin-4-yloxy)-indole-1 - carboxylic acid; (5-cyclopropylisoxazol-3-yl)-amide 5-((5)-6,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid acids; (4,4-dimethyl-5,6-dihydro-4H-pyrrolo|1,2-Bb|pyrazol-2-yl)-amide 5-((5)-7-ethyl-b-methyl-5,6, 7,8-tetrahydropyridoyi3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid; (5-cyclopropylisoxazol-3-yl)-amide (-)-5-((5)-7-acetyl-b-methyl-5,6,7,8-tetrahydropyridoi|3,4- a|pyrimidine-4- yloxy)-indole-1-carboxylic acid; 4-methyl-(5-cyclopropylisoxazol-3-yl)-amide 5-((5)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-4|pyrimidin-4-yloxy)-indole-1 - carboxylic acid;

15-(1-trifluoromethylcyclopropyl)-isoxazol-3-yl|-amide /5-((5)-6-methyl-5,6,7,8-tetrahydropyridoi|3,4-a|pyrimidin-4-yloxy) -indole-1-carboxylic acid; (1-tert-butyl-1H-pyrazol-3-yl)-amide 5-((5)-6-methyl-5,6,7,8-tetrahydropyrido|3,4-4|pyrimidin-4-yloxy) -indole-1-carboxylic acid; (5-Cyclopropylisoxazol-3-yl)-amide 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-4-methylindole-1-carboxylic acid;

15-(1-trifluoromethylcyclopropyl)-isoxazol-3-yl|-amide of 5-(6,7-dihydro-5H-pyrroloi|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid;

I5-(1-trifluoromethylcyclopropyl)-isoxazol-3-yl|-amide 5-(6,7,8,9-tetrahydro-5H-pyrimido|4,5-c|azepin-4-yloxy)-indol-1- carboxylic acid;

14-methyl-5-(1-methylcyclopropyl)-isoxazol-3-yl|-amide 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indol-1- carboxylic acid; (5-cyclopropylisoxazol-3-yl)-amide 5-(5)-7-acetyl-b-methyl-5,6,7,8-tetrahydropyridoi|3,4- a|pyrimidin-4-yloxy)-4- methylindole-1-carboxylic acid; 4-methyl-(5-cyclopropylisoxazol-3-yl)-amide 5-((5)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-4|pyrimidin-4-yloxy)-indole-1 - carboxylic acid; 5-(b-methylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (1-tert-butyl-1H-pyrazol-3-yl)y-amide; 5-(b-methylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-amide; (1-tert-butyl-1H-pyrazol-3-yl)-amide 5-(5)-7-acetyl-b-methyl-5,6,7,8-tetrahydropyridoi|Z3,4-a|pyrimidin-4 -yloxy)-indole-1-carboxylic acid; (5-Cyclopropylisoxazol-3-yl)-amide 5-((5)-7-butyryl-6-methyl-5,6,7 8-tetrahydropyrido3,4-a|pyrimidin-4-yloxy)-indol-1- carboxylic acid; (5-cyclopropylisoxazol-3-yl)-amide 5-((5)-6-methyl-7-propionyl-5,6,7,8-tetrahydropyrido3,4-a|pyrimidin-4-yloxy)-indole-1 - carboxylic acid; 4-1-(5-cyclopropylisoxazol-3-ylcarbamoyl)-1H-indol-5-yloxy|-5,6,7,8-tetrahydropyrido[3,4-4|pyrimidine-b6-carboxylic acid methylamide;

M-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-(2-(methylamino)methyl)pyridin-4-yloxy)-1H-indole-1-carboxamide; 5-(6-methylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (1,5-dicyclopropyl-1H-pyrazol-3-yl)-amide; 5-(6-methylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (5-cyclopropyl-1-ethyl-1H-pyrazol-3-yl)-amide; (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-amide 4-methyl-5-((5)-6-methyl-5,6,7,8-tetrahydropyridoyi3,4-4|pyrimidine -4-yloxy)-indole-1-carboxylic acid; and to a tautomer thereof and/or a pharmaceutically acceptable salt thereof.

For the purposes of this specification, the following definitions are used and, when appropriate, terms used in the singular include the plural and vice versa.

As used herein, the term "alkyl" means a fully saturated branched or unbranched hydrocarbon moiety. Preferably, if alkyl includes from 1 to 20 carbon atoms, more preferably from 1 to 16 carbon atoms, from 1 to 10 carbon atoms, from 1 to 7 carbon atoms or from 1 to 4 carbon atoms. Typical examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl , 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc.

As used herein, the term "haloalkyl" means an alkyl as defined herein substituted with one or more halide groups defined herein.

Preferably, if haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkyl, including perhaloalkyl. Monohaloalkyl can contain one atom of iodine, bromine, chlorine or fluorine in the alkyl group. Dihaloalkyl and polyhaloalkyl groups may contain two or more identical halogen atoms in the alkyl group or be a combination of different halide groups with alkyl. Preferably, if the polyhaloalkyl contains up to 12, or 10, or 8, or b, or 4, or 3, or 2 halide groups. Non-limiting examples of haloalkyls include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. Perhaloalkyl means an alkyl in which all hydrogen atoms have been replaced by halogen atoms.

The term "aryl" means monocyclic or bicyclic aromatic hydrocarbon groups containing 6-20 carbon atoms in the ring fragment. Preferably, if aryl means (C1-C:o)-aryl.

Non-limiting examples include phenyl, biphenyl, naphthyl, or tetrahydronaphthyl, each of which may optionally contain 1-4 substituents such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(O)-O-, aryl-O-, heteroaryl-O-, amino group, thio group, alkyl-5-, aryl-5-, nitro group, cyano group, carboxy group, alkyl-0O-C(0)-, carbamoyl, alkyl-5(O0)-, sulfonyl, sulfonamide group, heterocyclyl, etc.

Furthermore, the term "aryl" as used herein refers to an aromatic substituent which may be a single aromatic ring or multiple aromatic rings fused to one another, covalently bonded, or bonded to a common group such as a methylene or ethylene moiety. The common linking group can also be carbonyl, as in benzophenone, or oxygen, as in diphenyl ether, or nitrogen, as in diphenylamine.

As used in this invention, the term "alkyl group" means alkyl-O-, where alkyl is defined above in this invention. Typical examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy, cyclohexyloxy, and the like. Preferably, if the alkoxy groups contain about 1-7, more preferably about 1-4 carbon atoms.

As used herein, the term "alkanoyl" means a K-C(O0)- group containing from 1 to 1 carbon atoms, having a linear, branched or cyclic configuration, or a combination thereof, attached to the main structure via a carbonyl group. KE in the alkanoyl residue denotes hydrogen, alkyl, cycloalkyl or cycloalkylalkyl.

As used herein, the term "carbamoyl" means NoaMC(O)-, alkyl-MNO(O)-, (alkyl)2-MC(O)-, aryl-MNO(O)-, alkyl(aryl)-MC( 0)-, heteroaryl-"MHO(O)-, alkyl(heteroaryl)-MC(O)-, arylalkyl-MHC(O)- and alkyl(arylalkyl)-MC(O)-.

As used herein, the term "sulfonyl" means K-5052-, where K is hydrogen, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxy, aryloxy, cycloalkyl, or heterocyclyl.

When used in this invention, the term "sulfonamide group" means alkyl-5(0)2-MH-, aryl-

C(0)2-MH-, arylalkyl-5(0)2-MH-, heteroaryl-5(0)2-MH-, heteroarylalkyl-5(0)2-MH-, alkyl-5(O)"-

M(alkyl)-, aryl-5(0)2-M(alkyl)-, arylalkyl-5(O0)2-M(alkyl)-, heteroaryl-5(0)2-M(alkyl)- and heteroarylalkyl- 5(O0)2-M(alkyl)-.

As used herein, the term "heterocyclyl" or "heterocyclo" means an optionally substituted saturated or unsaturated aromatic ring or ring system, for example, which is a 4-, 5-, 6- or 7-membered monocyclic, 7- , 8-, 9-, 10-, 11- or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system and contains at least one heteroatom selected from from the group consisting of o, 5 and M, where M and 5 may optionally be oxidized to different oxidation states. A heterocyclic group can be attached through a heteroatom or a carbon atom. Heterocyclyl may include fused or bridged rings as well as spirocyclic rings. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane and thiomorpholine.

The term "heterocyclyl" also means heterocyclic groups defined in this invention containing 1,2 or C substituents selected from the group consisting of the following: (a) alkyl; (B) a hydroxy group (or a protected hydroxy group); (c) halogen; (a) oxo group, i.e. 0; (e) an amino group, an alkylamino group or a dialkylamino group; (I) an alkoxy group; (9) cycloalkyl; (n) carboxyl group; () a heterocyclooxy group, where a heterocyclooxy group means a heterocyclic group attached through an oxygen bridge;

(Y) alkyl-O-C(O)-; (Kk) mercapto group; (I) nitro group; (t) cyano group; (n) sulfamoyl or sulfonamide group; (o) aryl; (p) alkyl-C(0)-O-; (4) aryl-C(O)-O-; () aryl-5-; (5) an aryloxy group; () alkyl-5-; (y) formyl, i.e. HC(O)-; (m) carbamoyl; (m) arylalkyl-; and (x) aryl substituted with alkyl, cycloalkyl, hydroxy, hydroxy, amino, alkyl-

С(О)-МН-, an alkylamino group, a dialkylamino group or a halogen.

As used herein, the term "cycloalkyl" means saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon groups containing 3-12 carbon atoms, preferably 3-9 or 3-7 carbon atoms, each of which may optionally contain 1, 2 or 3, or a greater number of substituents, such as alkyl, halogen, oxo group, hydroxy group, alkoxy group, alkyl-C(O)-, acylamino group, carbamoyl, alkyl-MH-, (alkyl)2M-, thio group, alkyl-5- , nitro group, cyano group, carboxy group, alkyl-O-C(0)-, sulfonyl, sulfonamide group, sulfamoyl, and heterocyclyl. Typical monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl. Typical bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo/2.1.1|)hexyl, bicyclo|2.2.1)heptyl, bicyclo|2.2.1|)heptenyl, 6,6b-dimethylbicyclo!|3.1. 1)heptyl, 2,6,6-trimethyl-bicyclo|3.1.1|)heptyl and bicyclo|2.2.2|octyl. Typical tricyclic hydrocarbon groups include adamantyl.

When used in this invention, the term "sulfamoyl" means H2gM5(O)2-, alkyl-MHO(O) 2-, (alkyl)2-M5(O)2-, aryl-MHB(O) 2-, alkyl(aryl )-М5(О)2-, (aryl)2-М5(О)2-, heteroaryl-МНБ(О) 2-, (arylalkyl)-

МНО(О)»2- and (heteroaryl-alkyl)-МНО(О) 2-.

As used herein, the term "aryloxy" means both -O-aryl and -O-heteroaryl, where aryl and heteroaryl are defined herein.

As used herein, the term "heteroaryl" means a 5- to 14-membered monocyclic or bicyclic or polycyclic ring system containing from 1 to 8 heteroatoms selected from the group consisting of M, O, and 5. Preferably, if heteroaryl is a 5- to 10-membered or 5- to 7-membered ring system. Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4- or 5-pyrazinyl, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl.

The term "heteroaryl" also means a group in which the heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclic rings in which the radical or position of attachment is in the heteroaromatic ring. Non-limiting examples include, but are not limited to, 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl , 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 4-, 5-, 6- , 7- or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinolisinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3 -, 4-, 5- or b-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-daH-carbazolyl, 1-, 2-, 3-, 4 -, 5B-, 6-, 7- or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4 -, 6-, 7-, 8-, 9- or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 1-, 2 -, 4-, 5-, 6-, 7-, 8- or 9-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinyl, 1-, 2 -, 3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenothiazinyl, 1 -, 2-, 3-, 4-, 6- , 7-, 8-, 9- or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10- benzisoquinolinyl, 2-, 3-, 4- or thieno(2,3-b|furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H- pyrazino|2,3-s|carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furoi|3,2-5|-pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido|2,3-4|-o-oxazinyl, 1-, 3-, or 5-1H-pyrazolo|4,3-4|-oxazolyl, 2-, 4- or 54H-imidazoi|4,5- a|hiazolyl, 3-, 5- or 8-pyrazino|2,3-4|pyridazinyl, 2-, 3-, 5- or b-imidazo|2,1-Bb| hiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo!i3,4-c|cinolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10- or 11-4H-pyrido|2,3-sicarbazolyl, 2-, 3-, 6- or 7-imidazo|1,2-8111,2,griazinyl, 7-benzo|Bigienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6- or 7-benzothiazolyl, 1- , 2-, 4-, 5B-, 6-, 7-, 8- or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7- or 8-benzoxazinyl, 1-, 2-, 3- , 5-, 6-, 7-, 8-, 9-, 10- or 11-1H-pyrrolo(1,2-5I(2|benzazapinyl.

Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7 - or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or

7-benzoib|hienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl, 2-, 4-, 5-, 6- or 7- benzothiazolyl.

The heteroaryl group can be mono-, bi-, tri- or polycyclic, preferably mono-, bi- or tricyclic, more preferably mono- or bicyclic.

As used herein, the term "halogen" or "halogen" means fluorine, chlorine, bromine, and iodine.

As used herein, the term "isomers" refers to different compounds that have the same molecular formula but differ in the arrangement and configuration of atoms. Furthermore, as used herein, the term "optical isomer" or "stereoisomer" means any of the various stereoisomeric configurations that may exist for a given compound of the present invention, and includes geometric isomers. It should be understood that the substituent can be attached to a carbon atom that is a chiral center. Therefore, the present invention includes enantiomers, diastereoisomers and racemates of the compound. "Enantiomers" are pairs of stereoisomers that are non-superimposable mirror images of one another. A 1:1 mixture of two enantiomers of a compound is called a "racemic" mixture. This term is used to refer to a racemic mixture when appropriate. "Diastereoisomers" are stereoisomers that contain at least two asymmetric atoms, but which are not mirror images of one another. The absolute stereochemical configuration is described using K-5 of the Kahn-Ingold-Prelog system. If a compound is enantiomerically pure, then the stereochemical configuration of each chiral carbon atom can be described as K or 5.

Isolated compounds, the absolute configuration of which is not established, can be described with the symbols (g) or (-), depending on the direction in which they rotate the plane of polarization of light at the wavelength of the sodium O line (dextrorotatory or left-handed). Some of the compounds described in this invention contain one or more asymmetric centers and therefore can form enantiomers, diastereoisomers and other stereoisomeric forms, the absolute stereochemical configuration of which can be designated as (K)- or (5)-. The scope of this invention includes all such possible isomers, including racemic mixtures, optically pure forms, and mixtures of intermediates. Optically active (K)- and (5)- isomers can be obtained with the help of chiral synthons or chiral reagents or isolated by conventional methods. If the compound contains a double bond, then the substituents can be in the E or 2 configuration. If the compound is a disubstituted cycloalkyl, then the cycloalkyl substituents can be in the cis- or trans-configuration. All tautomeric forms are intended to be within the scope of this invention.

As used herein, the term "pharmaceutically acceptable salts" refers to salts which retain the biological efficacy and properties of the compounds of the present invention and which are not biologically or otherwise undesirable. In many cases, the compounds proposed in this invention can form salts with acid and/or base due to the presence of amino groups and/or carboxyl groups or similar groups. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and with organic acids, for example, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edizylate, hesylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, gibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethinoate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrophosphate/dihydrophosphate, saccharate, stearate, succinate, tartrate, tosylate, and trifluoroacetate. Inorganic acids from which salts can be formed include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be formed include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be formed include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum bases; ammonium, potassium, sodium, calcium and magnesium salts are particularly preferred. Organic bases from which salts can be formed include, for example, primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins, preferably such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Pharmaceutically acceptable salts proposed in this invention can be synthesized from the parent compound, basic or acidic fragment by conventional chemical techniques. Usually, such salts can be obtained by reacting the free acid forms of these compounds with a stoichiometric amount of the corresponding base (such as hydroxide, carbonate, bicarbonate, etc.

Ma, Ca, Md or K) or by the reaction of the free basic forms of these compounds with a stoichiometric amount of the corresponding acid. Such reactions are usually carried out in water or in an organic solvent or in their mixture. Of course, if possible, non-aqueous media such as ether, ethyl acetate, ethanol,

isopropanol or acetonitrile. Lists of additional suitable salts are given, for example, in the publication "Ketipdiopye Rpaptaseshisa! Zsiepse5", 201 units., Mask Rybriiepipu Sotrapu, Eazyup, Ra., (1985); and in "Naparook oi Rpaptasetshiisa! Zai5: Rgorepiev5, ZeIesiop, apa Oze" Bu ia! apa Uuegtshii (Uieu-msni, Meipneit, Septapu, 2002).

The scope of this invention includes all pharmaceutically acceptable isotopically labeled compounds of formula (I) in which (1) one or more atoms are replaced by atoms having the same atomic number but an atomic mass or a mass number different from the atomic mass or mass number normally found in nature, and/or (2) the ratios of the amounts of isotopes of one or more atoms differ from those found in nature.

Examples of isotopes suitable for incorporation into the compounds of the present invention include isotopes of hydrogen, for example 2H and 3H, carbon, for example C, 93C and "C, chlorine, for example

ZI, fluorine, for example, "ZE, iodine, for example, "23| and 729I, nitrogen, for example, "M and "M, oxygen, for example, 720, 170 and 780, phosphorus, for example, 32P, and sulfur, for example, 355.

Certain isotopically-labeled compounds of formula (I), for example, containing a radioactive isotope, are useful for studying the distribution of the drug and/or substrate in tissues. Radioactive isotopes of tritium, i.e. ZN, and carbon-14, i.e. "C" are particularly suitable for this purpose due to their ease of incorporation and simple means of detection.

Substitution with heavier isotopes such as deuterium, i.e., H, may result in some therapeutic advantages due to greater metabolic stability, such as increased half-life of ip mimo or the possibility of using lower doses, and therefore may be preferable in some circumstances. in the compounds of the formula K"e residues or rings formed using combinations of Ke and Co" can contain one or more deuterium atoms intended to increase the metabolic stability of the compound ip mimo.

Substitution with positron-emitting isotopes such as C, 9, 150, and ZM can be useful for studying substrate receptor occupancy using positron emission tomography (PET).

Isotopically labeled compounds of formula (I) can usually be prepared by standard methods known to those skilled in the art, or by methods analogous to those described in the examples and syntheses below, using a suitable isotopically labeled reagent instead of the previously used reagent that does not contain isotope

Pharmaceutically acceptable solvates in the context of this invention include those in which the crystallization solvent can be isotopically substituted, for example, 0 2 O, d-acetone, d-DMSO.

The compounds proposed in this invention, that is, the compounds of formula I, which contain groups capable of acting as donors and/or acceptors of hydrogen bonds, can form co-crystals with suitable substances that form co-crystals. These common crystals can be obtained from compounds of the formula !| according to known methods of co-crystallization. Such methods include grinding, heating, co-sublimation, co-melting or interaction in a solution of a compound of formula I with a substance that forms co-crystals, under conditions of crystallization with the selection of co-crystals formed in this way. Suitable co-crystal forming substances include those described in UMO 2004/078163. Therefore, the present invention also relates to joint crystals comprising a compound of formula I.

As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersing agents, coatings, surfactants, antioxidants, preservatives (eg, bactericidal agents, fungicidal agents), isotonic agents, absorption delaying agents ( see, e.g., Ketipdiopye Rnaptaseciis! Zsiepsev, 181st Es. Mask R'ipiipa Sotrapu, 1990, pp. 1289-1329, which is incorporated herein by reference). Unless the usual carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is intended.

The term "therapeutically effective amount" of a compound of the present invention means an amount of a compound of the present invention that results in a biological or medical response in a subject, such as a reduction or inhibition of enzyme or protein activity, or an alleviation of symptoms, attenuation pathological conditions, slowing down or delaying the progression or prevention of the disease, etc. In one non-limiting embodiment, the term "therapeutically effective amount" means an amount of a compound of the present invention that, when administered to a subject, is effective to (1) at least partially attenuate, inhibit, prevent, and/or ameliorate a pathological condition or disorder or disease , () mediated by MESE or its receptor, or (ii) associated with activity

MESBE or MESBE receptor activity, or (iii) characterized by abnormal activity of MESBE or its receptor; or (2) reducing or inhibiting the activity of MESE or its receptor; or (3) reducing or inhibiting the expression of MESE or its receptor. In another non-limiting embodiment, the term "therapeutically effective amount" means an amount of a compound of the present invention that, when administered to a cell or tissue or to a non-cellular biological substance or medium, is effective to at least partially reduce or inhibit the activity of MESE or its receptor; or at least to partially reduce or inhibit the expression of MESE or its receptor. The meaning of the term "therapeutically effective amount", illustrated in the above embodiment for MESE or its receptor, is the same with respect to any other suitable proteins/peptides/enzymes, such as Kei, ROSEC alpha and skii.

As used herein, the term "subject" means an animal. It is better if the animal is a mammal. Subject also means, for example, primates (eg humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In a preferred embodiment, the subject is a human.

As used herein, the term "inhibition" or "suppression" means the weakening or inhibition of a given pathological condition, symptom or disorder, or disease or significant weakening of the original biological activity or process.

As used herein, the term "treating" or "treating" any disease or disorder in one embodiment means ameliorating the course of the disease or disorder (ie, slowing, stopping, or attenuating the progression of the disease or at least one of its clinical symptoms). In another embodiment, "treating" or "treating" means improving at least one physical parameter, including those that may not be felt by the patient. In yet another embodiment, "treating" or "treating" refers to altering the course of a disease or disorder, either physical (eg, stabilization of an ongoing symptom) or physiological (eg, stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treating" means preventing or delaying the onset or development or progression of a disease or disorder.

As used in the present invention (especially in the claims), the terms used in the singular include the plural, and vice versa, unless otherwise specified in the present invention and unless clearly inconsistent with the context.

All of the techniques described herein may be performed in any suitable order unless otherwise specified herein and unless clearly inconsistent with the context. The use of any and all examples or indications of typical values (e.g., "such as") herein is intended merely to better describe the invention and is not intended to limit the scope of the invention as defined by the claims.

Any asymmetric atom (e.g., carbon, etc.) of the compound(s) of the present invention may be in racemic or enantiomerically enriched form, e.g., in the (K)-, (5)-, or (K, 5)-configuration . In some embodiments, each asymmetric atom is characterized by an enantiomeric excess in the (K)- or (5)-configuration of at least 50 95, an enantiomeric excess of at least 60 95, an enantiomeric excess of at least 70 95, an enantiomeric excess of at least 70 95 an excess of not less than 80 95, an enantiomeric excess of not less than 90 95, an enantiomeric excess of not less than 95 95, or an enantiomeric excess of not less than 99 95. Substituents of atoms forming a multiple bond, if possible, can be in cis- (727)- or trans (E)-form.

Therefore, when used in this invention, the compound proposed in this invention can be in the form of one of the possible isomers, rotators, atropisomers, tautomers or mixtures thereof, for example, in the form of essentially pure geometric (cis- or trans-) isomers, diastereoisomers , optical isomers (antipodes), racemates or their mixtures.

Using the differences in the physicochemical characteristics of the components, any resulting mixture of isomers can be separated into pure or mostly pure geometric or optical isomers, diastereoisomers, racemates, for example, by chromatography and/or fractional crystallization.

Any resulting racemates of final or intermediate products can be separated into optical antipodes by known techniques, for example, by separating the salts of their diastereoisomers obtained with an optically active acid or base, followed by isolation of the optically active acid or base. In particular, the main fragment can be used in this way to separate the compounds of the present invention into optical antipodes, for example, by fractional crystallization of a salt formed with an optically active acid, for example, tartaric acid, dibenzoyltartaric acid, diadetyltartaric acid, di- O, O'-p-tolutartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be separated using chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral sorbent.

The compounds proposed in this invention are obtained in free form, in the form of a salt or in the form of their prodrug derivatives.

If the same molecule contains both a basic group and an acidic group, then the compounds proposed in this invention can also form internal salts, for example, zwitterionic molecules.

The present invention also relates to prodrugs of the compounds of the present invention that are readily converted to the compounds of the present invention. Prodrugs are an active or inactive compound that, after administration to a subject, chemically changes as a result of physiological effects such as hydrolysis, metabolism, etc., to the compound proposed in this invention. Methods of preparation and use of prodrugs and their applicability are well known to specialists in this field of technology. By nature, prodrugs can be divided into two non-exclusive categories, prodrugs-biological precursors and prodrugs-carriers. See the publication of Te Rgasiise oi Medisipa! Spetivigu, SI. 31-32 (Eds. Uuegptshii, Asadetis Rgez55, Zap Oiedo, Saiyi., 2001). Usually, prodrugs-biological precursors are compounds that are inactive or have low activity compared to the active drug compound and contain one or more protective groups, and are converted into the active form due to metabolism or solvolysis. Both the active form of the drug and any released metabolic product must have acceptably low toxicity.

Procarriers are drug compounds that contain a carrier fragment, for example, that improves absorption or localizes release at the site(s) of action. For such carrier prodrugs, it is preferred that the linkage between the drug moiety and the carrier moiety be covalent, the prodrugs are inactive or less active than the drug compound, and any carrier moiety released is reasonably non-toxic. In the case of prodrugs for which the carrier fragment is designed to enhance absorption, the release of the carrier fragment should usually be rapid. In other cases, it is preferable to use a fragment that provides slow release, for example, some polymers or other fragments, such as cyclodextrins. Prodrug carriers, for example, can be used to improve one or more of the following characteristics: increased lipophilicity, increased duration of pharmacological action, improved site-of-effect specificity, reduced toxicity and adverse reactions, and/or improved drug characteristics (e.g., stability, solubility in water, suppression of undesirable organoleptic or physicochemical characteristics).

For example, lipophilicity can be increased by esterification of (a) hydroxy groups with lipophilic carboxylic acids (e.g., a carboxylic acid containing at least one lipophilic moiety) or (B) carboxyl groups with lipophilic alcohols (e.g., an alcohol containing at least one lipophilic moiety, e.g., aliphatic alcohols ).

Typical prodrugs are, for example, esters of free carboxylic acids with 5-acyl derivatives of thiols and

O-acyl derivatives of alcohols or phenols, where acyl takes the meaning defined in this invention.

Pharmaceutically acceptable esters are preferred, which are converted into the original carboxylic acid by hydrolysis under physiological conditions, for example, below. alkyl esters, cycloalkyl esters, lower. alkenyl esters, benzyl esters, mono- or disubstituted lower. alkyl esters, such as c" (amino-, mono- or di-lower. alkylamino-, carboxy-, lower. alkoxycarbonyl)-lower. alkyl esters, a-(lower. alkanoyloxy-, lower. alkoxycarbonyl- or di- lower. alkylaminocarbonyl)-lower. alkyl esters, such as pivaloyloxymethyl ether, etc. techniques commonly used in this field. In addition, amines are masked by the formation of arylcarbonyloxymethyl derivatives, which are quickly cleaved by esterases with the release of the free drug and formaldehyde (Vypadaaga, )U. Honey. Spent 2503 (1989)). In addition, medicinal products containing an acidic MH group, such as imidazole, imidine, indole, etc., are masked by

M-acyloxymethyl groups (Vipiddaaga, Oevidp oyi Rgodgidv, Eibemieg (1985)). Hydroxy groups are masked by the formation of complex and simple esters. EP 039051 (5iIosap apa I iShe) discloses prodrugs that are Mannich bases of hydroxamic acids, their preparation and use.

In addition, the compounds proposed in this invention, including their salts, can also be obtained in the form of their hydrates or with the inclusion of other solvents used for their crystallization.

Another object of the present invention is a pharmaceutical composition containing a compound of the present invention and a carrier, for example, a pharmaceutically acceptable carrier. The pharmaceutical composition can be formulated for specific routes of administration, such as oral administration, ocular administration (e.g., topical administration, vitreous injection), implant administration (including intravitreous, transscleral, subtenon space, etc., depot form, etc.) and parenteral administration, etc. In addition, the pharmaceutical compositions provided in the present invention can be prepared in solid form, including capsules, tablets, pills, granules, powders, or suppositories, or in liquid form, including solutions, suspensions, or emulsions

Pharmaceutical compositions may be subjected to conventional pharmaceutical processing, such as sterilization, and/or they may contain conventional inert diluents, lubricating agents or buffering agents, as well as excipients such as preservatives, stabilizers, wetting agents, emulsifiers and buffering agents, and the like.

Typically, pharmaceutical compositions are tablets or capsules made of gelatin, including the active ingredient, as well as a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;

p) lubricating agents, for example, silicon dioxide, talc, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; for tablets also c) binders, for example, magnesium aluminosilicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium salt of carboxymethylcellulose and/or polyvinylpyrrolidone; if necessary a) leavening agents, for example, starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, dyes, flavors and sweeteners.

Film coating or enteric coating can be applied to tablets by techniques known in the art.

Compositions suitable for oral administration include an effective amount of a compound of the present invention in the form of tablets, cakes, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups, or elixirs. Compositions intended for oral administration are prepared by any technique known in the art for the preparation of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavorings, coloring agents, and preservatives to to obtain pharmaceutical attractive drugs that have a pleasant taste. The tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable inert excipients which are suitable for making tablets. These inert fillers are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and leavening agents, for example, corn starch or alginic acid; binding agents, for example, starch, gelatin or acacia gum; and lubricating agents such as magnesium stearate, stearic acid or talc. The tablets are uncoated or are coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, which provides a continuous effect over a longer period of time. For example, a retarding agent such as glyceryl monostearate or glyceryl distearate can be used. Oral preparations may also be hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules in which the active ingredient is mixed with water or oil medium, such as peanut oil, liquid paraffin or olive oil.

Some compositions for injections are isotonic aqueous solutions or suspensions, and suppositories are mainly prepared from emulsions or suspensions of fats. These compositions can be sterilized and/or have auxiliary substances added to them, such as preservatives, stabilizers, wetting or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure and/or buffering agents. In addition, they may also contain other therapeutically valuable substances. These compositions are prepared by conventional mixing, granulating or coating techniques and contain approximately 0.1-75%, or contain approximately 1-50%, of the active ingredient.

Some injectable compositions include ophthalmic implant and ophthalmic depot preparations that are suitable for intraocular, intraocular, subconjunctival, or subtenon administration.

Usually, compositions for injection contain a compound of formula (I) in combination with a biocompatible or biodegradable polymeric material.

Compositions suitable for transdermal administration include an effective amount of a compound of the present invention with a carrier. Preferred carriers include pharmacologically acceptable absorbable solvents that facilitate penetration through the recipient's skin. For example, transdermal delivery devices are a dressing that includes a protective layer, a reservoir that contains the compound optionally with carriers, optionally a barrier that regulates the delivery of the compound through the recipient's skin at a predetermined rate over an extended period of time, and a means of securing the device to the skin.

Compositions suitable for topical administration, e.g. to the skin or eyes, include aqueous solutions, suspensions, ointments, creams, gels or spray compositions, e.g. for administration as an aerosol and the like. Such topical devices are particularly suitable for use in the eye, for example, for the treatment of diseases of the eye, for example, for prophylactic or therapeutic use in the treatment of macular degeneration, diabetic retinopathy, iris redness, revascularization of the cornea, sclera, retina or other tissue of the eye, and the like. They are therefore particularly suitable for use in topical agents well known in the art. They may contain solubilizers, stabilizers, tonicity-regulating agents, buffering agents, and preservatives.

Some suitable topical eye drop preparations are an aqueous solution or aqueous suspension of a compound of formula I and optionally additionally contain one or more preservatives, tonicity-regulating agents, and/or lubricants.

When used in the present invention, local administration can also be inhalation or nasal administration. The usual administration is carried out in the form of a dry powder (separately or in the form of a mixture, for example, a dry mixture with lactose, in the form of mixtures with components, for example, with phospholipids) using an inhaler for dry powders or in the form of an aerosol spray supplied from a container that is under pressure, by means of a pump, spray device, atomizer or nebulizer type device with or without the use of a suitable propellant.

The present invention also relates to anhydrous pharmaceutical compositions and dosage forms containing the compounds of the present invention as active ingredients, since water can facilitate the decomposition of some compounds.

Anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous ingredients or ingredients having low moisture content under low humidity conditions. An anhydrous pharmaceutical composition can be prepared and stored so that it remains anhydrous. Accordingly, anhydrous compositions should preferably be packaged in materials known to be water resistant so that they can be incorporated into suitable formulation kits. Examples of suitable packaging materials include, but are not limited to, hermetically sealed foil, plastics, single-dose containers (eg, vials), blister packs, and tape packaging.

The present invention also relates to pharmaceutical compositions and dosage forms that include one or more agents that reduce the rate at which a compound of the present invention will be degraded as an active ingredient. Such agents, referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH-adjusting buffering agents, or salt buffering agents, and the like.

The compounds of formula I in free form or in the form of a pharmaceutically acceptable salt have valuable pharmacological properties, for example, the ability to modulate the MESE receptor, for example, as shown by the ip myo and ip mimo studies presented in the following sections, and are therefore useful for treatment.

Due to the fact that the compounds of the formula I are active inhibitors of the MESE receptor, the compounds of the formula ! are particularly suitable for the treatment of diseases associated with impaired regulation of angiogenesis, especially diseases caused by ocular revascularization, mainly retinopathy, such as diabetic retinopathy or age-related macular degeneration, iris redness, psoriasis, Hippel-Lindau disease, hemangioblastoma, angioma, mesangial proliferative cellular disorders, such as chronic or acute kidney diseases, for example, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes or transplant rejection, or especially inflammatory kidney disease, such as glomerulonephritis, mainly mesangioproliferative glomerulonephritis, hemolytic uremic syndrome, diabetic nephropathy, hypertensive nephrosclerosis, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, fibrous disorders (for example, liver cirrhosis), diabetes, endometriosis, chronic asthma, arterial or post-transplant atherosclerosis neurodegenerative disorders and mainly tumor diseases (mainly solid tumors, as well as leukemias), mainly such as breast cancer, adenocarcinoma, colorectal cancer, lung cancer (mainly non-small cell lung cancer), kidney cancer, liver cancer, pancreatic cancer, cancer ovarian or prostate cancer, as well as myeloma, mainly multiple myeloma, myelodysplastic syndrome, AML (acute myelogenous leukemia), AMM (angiogenic myeloid metaplasia), mesothelioma, glioma and glioblastoma. The compound of the formula | is also particularly suitable for preventing the metastatic spread of tumors and the growth of micrometastases.

Thus, in another embodiment, the present invention relates to the use of compounds of formula (I) or its subformulas, for example, compounds of formula II or I, for treatment. In another embodiment, treatment is carried out for a disease selected from the list of diseases, the course of which is facilitated by inhibiting the activity of the MESE receptor. In another embodiment, the disease is selected from the above list, and is preferably an eye disease, more preferably wet and dry forms of age-related macular degeneration, geographic atrophy, central serous retinopathy, cystoid macular edema, diabetic retinopathy, proliferative diabetic retinopathy, diabetic edema macular, iris redness, retrolethal fibroplasia, central vein and retinal vein occlusions, inflammatory/infectious retinal revascularization/edema (eg, posterior uveitis, sarcoid, toxoplasmosis, histoplasmosis, Vogt-Konayaga-Harada disease, chronic uveitis, tuberculosis, syphilis, punctate and multifocal internal choroidopathy), retinoblastoma, melanoma, eye tumors, retinal detachment, myopic revascularization, retinal angioid bands, Ilse disease, ischemic retinopathy (retinal artery occlusion, Takayasu carotid occlusion), choroidal tear, wear-related disorders contact lenses, dry i. keratitis, blepharitis, corneal dystrophy, trauma and consequences of previous corneal surgery (corneal transplants, laser vision correction according to GI ABIK, GAZEK methods), corneal infections (bacterial, viral, parasitic, herpetic), corneal burns (chemical, alkaline, acid )

corneal transplant rejection, immunological disease of the cornea (pemphigoid, Stevens syndrome -

Johnson) and degenerative diseases of the cornea.

A pharmaceutical composition or combination of the present invention, for a subject weighing about 50-70 kg, may contain in a single dose about 1-1000 mg of the active ingredient(s), or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of active ingredients. A therapeutically effective dose of a compound, pharmaceutical composition, or combinations thereof depends on the subject's species, body weight, age, and the individual condition, disorder, or disease being treated, or its severity. A physician, clinician, or veterinarian with general training should readily determine the effective amount of each of the active ingredients necessary to prevent, treat, or inhibit the progression of a disorder or disease.

The above dose characteristics can be determined using ip mio and ip mimo studies, preferably using mammals, such as mice, rats, dogs, monkeys, or isolated organs, tissues, and preparations thereof. The compounds proposed in this invention can be used ip mio in the form of solutions, for example, preferably aqueous solutions, and ip mimo enterally, parenterally, preferably intravenously, for example, in the form of a suspension or an aqueous solution. The dose of ip mio can be in the range of about 103 to 109 M. A therapeutically effective amount of ip mimo depending on the route of administration can be in the range of about 0.1-500 mg/kg or about 1-100 mg/kg.

Other embodiments relate to a pharmaceutical composition that contains at least one compound described by any of formulas I, II, SH, IM, M or MI or subformulas thereof, and at least one carrier.

The combination of the formula and! can also be successfully used in combination with other antiproliferative agents. Such antiproliferative agents include, but are not limited to, aromatase inhibitors; anti-estrogens; topoisomerase I inhibitors; HER topoisomerase inhibitors; agents active on microtubules; alkylating agents; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; inhibitors that; antitumor antimetabolites; platinum compounds; compounds designed to selectively affect/reduce protein or lipid kinase activity and other antiangiogenic compounds; compounds that are designed to selectively affect/reduce or inhibit protein or lipid phosphatase activity; gonadorelin agonists; antiandrogens; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of oncogenic Kab isoforms; telomerase inhibitors; proteosome inhibitors; means used in the treatment of malignant blood diseases; means that are intended for selective influence, reduction or inhibition of E-3 activity; Nero0 inhibitors; temozolomide (TTEMODALF); and leucovorin.

A compound of Formula I may also be used successfully in combination with other eye treatments including, but not limited to, macugen, MESBE scavenger, photodynamic therapy, anecortav acetate, steroids, non-steroidal anti-inflammatory drugs (eg, naproxen, ibuprofen, diclofenac) , Sox-1 and Sox-2 inhibitors, cyclosporine, dexamethasone, tTOK (mammalian target of rapamycin) inhibitors such as rapamycin, everolimus, etc., PKC (protein kinase C) beta inhibitors, tumor necrosis alpha inhibitors, interleukin 1 -beta inhibitors, platelet growth factor receptor inhibitors beta and alpha, Lucentis, Avastin, antibodies to

MESE, antibodies to RICE, small interfering RNAs for the family of MESE (A-E, RIS, neuropilin) and/or receptors of MESE, complementary inhibitors that selectively affect classical and alternative lectin pathways, I--10 inhibitors, C5ak inhibitors, CZak inhibitors and sphingosine phosphate inhibitors and receptors.

The compound proposed in this invention can be administered simultaneously or before or after at least one other therapeutic agent. The compound proposed in this invention can be administered separately by the same or a different route of administration or together in the same pharmaceutical composition.

The term "aromatase inhibitor" as used herein means a compound that inhibits the production of estrogen, i.e., the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term preferably includes, but is not limited to, atamestane, exemestane, and formestane, and preferably nonsteroidal compounds, preferably aminoglutethimide, rogletimide, pyroglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane can be administered, for example, in the form in which it is sold, for example, under the trade name AROMAZIN. Formestane can be administered, for example, in the form in which it is sold, for example, under the trade name LENTARON. Fadrozole can be administered, for example, in the form in which it is sold, for example, under the trade name AFEMA. Anastrozole can be administered, for example, in the form in which it is sold, for example, under the trade name

ARIMIDEKS. Letrozole can be administered, for example, in the form in which it is sold, for example, under the trade name FEMARA or FEMAR. Aminoglutethimide can be administered, for example, in the form in which it is sold, for example, under the trade name ORIMETEN. The combination proposed in this invention, which includes a chemotherapeutic agent that is an aromatase inhibitor, is particularly suitable for the treatment of hormone-receptor-positive tumors, for example, breast tumors.

The term "antiestrogen" as used herein refers to a compound that counteracts the effects of estrogen at the estrogen receptor level. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen can be administered, for example, in the form in which it is sold, for example, under the trade name NOLVADEX.

Ralcosifene hydrochloride can be administered, for example, in the form in which it is sold, for example, under the trade name EVISTA. Fulvestrant can be prepared as disclosed in 05 4659516 or it can be administered, for example, in the form in which it is sold, for example under the trade name FAZLODEX. The combination proposed in this invention, which includes a chemotherapeutic agent that is an antiestrogen, is particularly useful for the treatment of estrogen receptor-positive tumors, for example, breast tumors.

The term "antiandrogen" as used herein refers to any compound capable of inhibiting the biological effects of androgenic hormones, and includes, but is not limited to, bicalutamide (CASODEX), which may be prepared, for example, as disclosed in O5 4636505.

The term "gonadorelin agonist" as used herein includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin is disclosed in 05 4100274 and can be administered, for example, in the form in which it is sold, for example, under the trade name

ZOLADEX. Abarelix can be prepared, for example, as disclosed in 5 5843901.

The term "topoisomerase I inhibitor" as used in this invention includes, but is not limited to, topotecan, himatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin and the macromolecular conjugate of camptothecin RMO-166148 (compound AT in UMO 99/17804 ). Irinotecan can be administered, for example, in the form in which it is sold, for example, under the trade name CAPMTOSAR. Topotecan can be administered, for example, in the form in which it is sold, for example, under the trade name HICAMTIN.

The term "topoisomerase I inhibitor" as used herein includes, but is not limited to, anthracyclines such as doxorubicin (including a liposomal formulation such as CAELIX), daunorubicin, epirubicin, idarubicin, nemorubicin, the anthraquinones mitoxantrone and lozoxantrone, and the podophyllotoxins etoposide and teniposide Etoposide can be administered, for example, in the form in which it is sold, for example, under the trade name ETOPOFOS. Teniposide can be administered, for example, in the form in which it is sold, for example, under the trade name UM 26-

VKI5TOI.. Doxorubicin can be administered, for example, in the form in which it is sold, for example, under the trade name ADRIBLASTIN or ADRIAMYCIN. Epirubicin can be administered, for example, in the form in which it is sold, for example, under the trade name FARMORUBICIN. Idarubicin can be administered, for example, in the form in which it is sold, for example under the trade name

FACTORY Mitoxantrone can be administered, for example, in the form in which it is sold, for example, under the trade name NOVANTRON.

The term "microtubule-active agent" refers to microtubule-stabilizing compounds, microtubule-destabilizing compounds, and microtubule polymerization inhibitors, and including, but not limited to, taxanes such as paclitaxel and docetaxel; periwinkle alkaloids, for example vinblastine, preferably vinblastine sulfate, vincristine, preferably vincristine sulfate and vinorelbine, discodermolides, colchicine and epothilones and their derivatives, for example epothilone B or O or their derivatives. Paclitaxel can be administered, for example, in the form in which it is sold, e.g.

TAXOL. Docetaxel can be administered, for example, in the form in which it is sold, for example, under the trade name TAXOTER. Vinblastine sulfate can be administered, for example, in the form in which it is sold, for example, under the trade name VINBLASTIN K.R. Vincristine sulfate can be administered, for example, in the form in which it is sold, for example under the trade name

PHARMACIST. Discodermolide can be prepared, for example, as disclosed in 05 5010099.

Also included are epothilone derivatives disclosed in UMO 98/10121, OO5 6194181, UMO 98/25929, UMO 98/08849, MO 99/43653, MO 98/22461 and MO 00/31247. Especially preferred are epothilone A and/or B.

The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, and nitrosourea (VSMIO or Gliadel).

Cyclophosphamide can be administered, for example, in the form in which it is sold, for example, under the trade name CYCLOSTIN. Ifosfamide can be administered, for example, in the form in which it is sold, for example, under the trade name HOLOXAN.

The term "histone deacetylase inhibitors" or "NOAA inhibitors" refers to compounds that inhibit histone deacetylase and that have antiproliferative activity. They include compounds disclosed in

UMO 02/22577, preferably M-hydroxy-3-(4-((2-hydroxyethyl)|2-(1H-indol-3-yl)ethyl|-amino|methyl|phenyl|- 2E-2-propenamide, M -hydroxy-3-(4-((2-(2-methyl-1 H-indol-3-yl)-ethyl|-amino|methyl|-phenyl|-2E-2-

propenamide and their pharmaceutically acceptable salts. They also preferably include hydroxamic acid suberoylanilide (SAGA).

The term "antitumor antimetabolite" includes, but is not limited to, 5-fluorouracil (5-PE)), capecitabine, gemcitabine, DNA demethylating agents such as 5-azacytidine and decitabine, methotrexate, edatrexate, and folic acid antagonists such as pemetrexed . Capecitabine can be administered, for example, in the form in which it is sold, for example under the trade name

XELODA. Gemcitabine can be administered, for example, in the form in which it is sold, for example, under the trade name GEMZAR. Also included is the monoclonal antibody trastuzumab, which can be administered, for example, in the form in which it is sold, for example under the trade name

HERCEPTIN.

The term "platinum compound" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatin, and oxaliplatin. Carboplatin can be administered, for example, in the form in which it is sold, for example, under the trade name CARBOPLAT.

Oxaliplatin can be administered, for example, in the form in which it is sold, for example, under the trade name ELOXATIN.

The term "selectively acting/lowering protein or lipid kinase activity and other anti-angiogenic compounds" as used herein includes, but is not limited to: protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, for example: a) compounds that selectively act, reduce or inhibit the activity of fibroblast growth factor receptors (ЕСЕ-Н5); p) compounds that selectively act, reduce or inhibit the activity of the insulin-like growth factor I receptor (IGF-IC), preferably compounds that inhibit IOB-IC, such as the compounds disclosed in UMO 02/092599; c) compounds that selectively act, reduce or inhibit the activity of the TIC receptor of the tyrosine kinase group; a) compounds that selectively act, reduce or inhibit the activity of the Ahi receptor of the tyrosine kinase group; e) compounds that selectively act, reduce or inhibit the activity of the c-Mei receptor;

Ж) compounds that selectively act, reduce or inhibit the activity of representatives of protein kinases C (RKS) and the group of Kai serine/threonine kinases, representatives of MEK, 5KS, UAK, RAK, ROK and representatives of the group

Kaz/MARK, or a group of RI(3) kinases, or a group of RI(3)-kinase-related kinases, and/or representatives of the group of cyclin-dependent kinases (SOK) and especially staurosporine derivatives disclosed in 5 5093330, for example, midostaurin; examples of other compounds include, for example, SHSM-01; safingol; VAM 43-9006; bryostatin 1; perifosine; ilmofosine; KO 318220 and KO 320432; 050 6976; Ivib5 3521;

And X333531/. 379196; isoquinoline compounds, such as disclosed in M/O 00/09495; ETI5; RO184352; and OAMb697 (RIZK inhibitor); 9) compounds that selectively reduce or inhibit the activity of protein tyrosine kinase inhibitors, such as compounds that are designed to reduce or inhibit the activity of protein tyrosine kinase inhibitors, including imatinib mesylate (GLIVEK/L/LEEVEK) and tyrphostin.

Tyrphostin is preferably a compound with a low molecular weight (Mg<1500) or a pharmaceutically acceptable salt thereof, preferably a compound selected from the group comprising the class of benzylidenemalonitriles or the class of 5-arylbenzenemalonitriles or the class of bisubstrate quinolines, more preferably any compound selected from from the group including tyrphostin A23/K0-50810, AC 99, tyrphostin AC 213, tyrphostin AC 1748, tyrphostin AC 490, tyrphostin B44, tyrphostin B44 (t) enantiomer, tyrphostin AC 555, AC 494, tyrphostin AC 556, ASU57 and adafostin (adamantyl ether of 4(2,5dihydroxyphenyl)methyliamino)-benzoic acid, MZS 680410, adafostin); and

J) compounds that selectively act, reduce or inhibit the activity of a group of receptors of epidermal growth factors receptor tyrosine kinases (ESEK, EgrB2, EgB3Z, EgBBA in the form of homo- and heterodimers), such as compounds that selectively act, reduce or inhibit the activity of a group of receptors of epidermal growth factors growth factors, preferably compounds, proteins or antibodies that inhibit representatives of the ECE receptor tyrosine kinase group, for example, the ECE receptor, EgrB2, EgB3 and EgB4 or bind to ligands related to ESE or ESE ligands, and preferably are such compounds, proteins or monoclonal antibodies, which are generally and specifically disclosed in UMO 97/02266, for example, the compound of example 39, or in EP 0564409, UMO 99/03854, EP 0520722, EP 0566226,

EP 0787722, EP 0837063, 05 5747498, UMO 98/10767, MO 97/30034, UMO 97/49688, UMO 97/38983 and especially in MO 96/30347 (for example, the compound known as SR 358774), MUMO 96 /33980 (for example, compound 20 1839), and UMO 95/03283 (for example, compound 2M105180); for example, trastuzumab (HERCEPTIN), cetuximab, iressa, erlotinib (targeted!)), SI-1033, EKV-569, SMU-2016, E1.1, E2.4,

E2.5, Eb6.2, Eb.4, E2.11, Eb.3 or E7.6.3; and derivatives of 7H-pyrrolo-(2,3-4|Ipyrimidine), which are disclosed in UUO 03/013541.

Other antiangiogenic compounds include compounds characterized by a different mechanism of action, for example, that does not involve inhibition of protein or lipid kinase, for example, thalidomide (TALOMID) and TMP-470.

Compounds that selectively act, reduce or inhibit the activity of protein or lipid phosphatase, are, for example, inhibitors of phosphatase 1, phosphatase 2A, RTEM or COS25, for example, okadaic acid or its derivatives.

Compounds that induce cell differentiation processes are, for example, retinoic acid, α-y- or β-tocopherol or α-y- or β-tocotrienol.

The term "cyclooxygenase inhibitor" as used herein includes, but is not limited to, e.g., Cox-2, 5-alkyl substituted 2-arylaminophenylacetic acid inhibitors and derivatives such as celecoxib (CELEBREX), rofecoxib (VIOX), etoricoxib, valdecoxib and 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6-fluoroamino)phenylacetic acid and lumiracoxib.

The term "ttToC inhibitors" refers to compounds that inhibit the target of rapamycin (ttTOC) in mammals and that have antiproliferative activity, such as sirolimus (rapamun"Mm), everolimus (certican M), SCI-779 and AVT578.

The term "bisphosphonates" as used herein includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zolendronic acid. "Etridronic acid" can be administered, for example, in the form in which it is sold, for example, under the trade name DIDRONEL. "Clodronic acid" can be administered, for example, in the form in which it is sold, for example, under the trade name BONEFOS. "Tiludronic acid" can be administered, for example, in the form in which it is sold, for example, under the trade name SCELID. "Pamidronic acid" can be administered, for example, in the form in which it is sold, for example, under the trade name AREDIA"M. "Alendronic acid" can be administered, for example, in the form in which it is sold, for example, under the trade name

FOSAMAX. "Ibandronic acid" can be administered, for example, in the form in which it is sold, for example, under the trade name BONDRANAT. "Risedronic acid" can be administered, for example, in the form in which it is sold, for example, under the trade name ACTONEL. "Zolendronic acid" can be administered, for example, in the form in which it is sold, for example, under the trade name ZOMETA.

The term "heparinase inhibitor" as used herein refers to compounds that selectively act to reduce or inhibit the breakdown of heparin sulfate. The term includes, but is not limited to, RI-88.

The term "biological response modifier" as used herein means a lymphokine or interferons, for example, interferon a.

The term "inhibitor of oncogenic Kavz isoforms", for example, H-Vaz, K-Kah, or M-Kav, as used in this invention means compounds that selectively act, reduce or inhibit oncogenic activity

Kav, for example, "inhibitor of farnesyltransferase", for example, I-744832, YuK8O557 or K115777 (zarnestra).

The term "telomerase inhibitor" as used herein refers to compounds that selectively act to reduce or inhibit telomerase activity. Compounds that selectively reduce or inhibit telomerase activity are preferably compounds that inhibit the telomerase receptor, for example, telomestatin.

The term "methionine aminopeptidase inhibitor" as used herein means compounds that selectively act to reduce or inhibit the activity of methionine aminopeptidase. Compounds that selectively act, reduce or inhibit the activity of methionine aminopeptidase, are, for example, bengamide or its derivatives.

The term "proteosome inhibitor" as used herein refers to compounds that selectively act to reduce or inhibit the activity of the proteosome. Compounds that selectively reduce or inhibit proteosome activity include, for example, PO-341 and MI-M 341.

The term "matrix metalloproteinase inhibitor" or "MMP inhibitor" as used herein includes, but is not limited to, peptidomimetic and non-peptidomimetic collagen inhibitors, tetracycline derivatives, for example, the peptidomimetic hydroxamate inhibitor batimastat and its orally bioavailable analog, marimastat (VV-2516), prinomastat (АС3340), metastat (М5С 683551) ВМ5-279251, VAM 12-9566, TAA211, ММИ27ОВ or

AASHZOIB.

The term "agents used in the treatment of blood malignancies" as used herein includes, but is not limited to, EM5-like tyrosine kinase inhibitors, for example, compounds that selectively reduce or inhibit EI-3 activity; interferon, 1-6-0-arabinofuransylcytosine (aga-c) and bisulfan; and alkyl inhibitors, eg, compounds that selectively act to reduce or inhibit anaplastic lymphoma kinase.

The term "compounds that selectively act, reduce or inhibit EC-3 activity" preferably means compounds, proteins or antibodies that inhibit EC-3, for example, PKS412, midostaurin, staurosporine derivative, 5011248 and MI M518.

The term "NOROO inhibitors" when used in this invention includes, but is not limited to, compounds that selectively act, reduce or inhibit the specific ATPase activity of H5POO; destroy selectively acting, reducing or inhibiting the client proteins of the NKROO via the ubiquitin pathway of the proteosome. Compounds that selectively reduce or inhibit specific ATPase activity

H5POOs are preferably compounds, proteins or antibodies that inhibit the specific ATPase activity of NBRO0O, for example, 17-allylamino, 17-demethoxygeldanamycin (17AAS), a geldanamycin derivative, other geldanamycin-related compounds, radicicol, and NOAS inhibitors.

The term "antiproliferative antibodies" as used herein includes, but is not limited to, trastuzumab (Herceptin M), trastuzumab-OMI1, ranibizumab (Lucentisf)), bevacizumab (Avastin M), rituximab (Rituxan M), RKOb4553 (anti-CO40) and 204 antibodies.Antibodies include, for example, intact monoclonal antibodies, polyclonal antibodies, polyvalent antibodies formed from at least two intact antibodies, and antibody fragments, if they have the necessary biological activity.

For the treatment of acute myelogenous leukemia (AML), the compounds of formula (I) can be used in combination with standard anti-leukemic drugs, preferably in combination with drugs used for the treatment of AML. In particular, compounds of formula (I) can be administered in combination, for example, with farnesyltransferase inhibitors and/or other drugs used to treat AML, such as daunorubicin, adriamycin, Aga-C, MP-16, teniposide, mitoxantrone, idarubicin, carboplatin and РКСА12.

The structure of active agents that have code numbers, generic or trade names is given in the latest edition of the Pharmacopoeia Handbook and in databases, for example, Pharmacopoeia (for example, IM5 UMogiya Rybriisayopv5).

The above compounds which can be used in combination with a compound of formula I can be prepared and administered as described in the art, for example in the documents cited above.

The compound of formula I can also be successfully used in combination with known therapeutic agents, for example, with the introduction of hormones or, preferably, irradiation.

The compound of formula Y, in particular, can be used as a radiosensitizing agent, preferably for the treatment of tumors that have a poor sensitivity to radiation therapy.

In one embodiment, the present invention relates to a product containing a compound of formula (I) and at least one other therapeutic agent, in the form of a combined composition for simultaneous, separate or sequential use for treatment. In one embodiment, the treatment is the treatment of a disease or pathological condition mediated by the activity of MESE or the MESE receptor. Products supplied as a combined preparation contain a composition including a compound of formula (I) and another therapeutic agent(s) in the same pharmaceutical composition, or a compound of formula (I) and another therapeutic agent(s) in separate forms , for example, in the form of a set.

In one embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and another therapeutic agent(s). The pharmaceutical composition may optionally include a pharmaceutically acceptable inert excipient as described above.

In one embodiment, the present invention relates to a kit including two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (1).

In one embodiment, the kit includes a device for separate storage of said compositions, such as a container, divided vial, or divided foil bag. An example of such a set is blister packaging, which is usually used for packaging tablets, capsules, etc.

The set proposed in the present invention can be used to administer different dosage forms, for example, oral and parenteral, to administer separate compositions at different intervals, or to prevent contact of separate compositions with one another. To facilitate patient compliance, the kit provided in the present invention typically includes an administration guide.

In the combination therapy provided by the present invention, the compound provided by the present invention and another therapeutic agent may be manufactured and/or prepared by the same or different manufacturers. In addition, a compound of the present invention and another therapeutic agent may be combined in a combination product: (i) prior to providing the combination product to physicians (e.g., in the case of a kit comprising a compound of the present invention and another therapeutic agent means); (ii) by the doctors themselves (or under the direction of the doctor) shortly before the introduction; (ii). in the patient himself, for example, during the sequential administration of the compound proposed in this invention and another therapeutic agent.

Accordingly, the present invention relates to the use of a compound of formula (I) for the preparation of a medicinal product intended for the treatment of a disease or pathological condition mediated by the activity of MESE or the MESE receptor, wherein the medicinal product is prepared for administration together with another therapeutic agent. The present invention also relates to the use of another therapeutic agent for the preparation of a medicinal product intended for the treatment of a disease or pathological condition mediated by the activity of MESE or the MESE receptor, where the medicinal product is prepared for administration together with a compound of formula (1).

The present invention also relates to a compound of formula (I) intended for use in a method of treating a disease or pathological condition mediated by the activity of MEC or the MEC receptor, where the compound of formula (I) is prepared for administration together with another therapeutic agent. The present invention also relates to another therapeutic agent intended for use in a method of treating a disease or pathological condition mediated by the activity of MESE or the MESE receptor, wherein the other therapeutic agent is prepared for administration together with a compound of formula (I). The present invention also relates to a compound of formula (I) intended for use in a method of treating a disease or pathological condition mediated by the activity of MESE or the MESE receptor, where the compound of formula (I) is administered together with another therapeutic agent. The present invention also relates to another therapeutic agent intended for use in a method of treating a disease or pathological condition mediated by the activity of MESE or the MESE receptor, where the other therapeutic agent is administered together with the compound of formula (1).

The present invention also relates to the use of a compound of formula (I) for the preparation of a medicinal product intended for the treatment of a disease or pathological condition mediated by the activity of MESE or the MESE receptor, in which the patient was previously (for example, no later than 24 hours) administered another therapeutic means. The present invention also relates to the use of another therapeutic agent for the preparation of a medicinal product intended for the treatment of a disease or pathological condition mediated by the activity

MESE or its receptor, in which the patient was previously (for example, no later than 24 hours) administered the compound of formula (1).

The following examples are intended to illustrate the present invention and should not be construed as limiting. Temperatures are indicated in degrees centigrade. Unless otherwise specified, all evaporations are carried out under reduced pressure, preferably at a pressure approximately equal to 15 mm Hg. Art. up to 100 mm Hg Art. (- 20-133 mbar). The structures of final products, intermediates, and starting materials are confirmed by standard analytical techniques, such as microanalysis and/or spectroscopic techniques (e.g., MS, IR (infrared spectroscopy), NMR).

Abbreviations used are as accepted in the art.

All starting materials, structural fragments, reagents, acids, bases, dehydrating reagents, solvents, and catalysts used in the synthesis of the compounds of this invention are commercially available or can be prepared by organic synthesis techniques known to those of ordinary skill in the art. engineering (Noibep-MUeu! 4 Ea. 1952, MeSshoadz oi Ogdapis zupipezi5, Tpiete, Moishte 21). In addition, the compounds of the present invention can be prepared by organic synthesis techniques known to one of ordinary skill in the art, as exemplified below.

Due to the fact that compounds of formula I are active inhibitors of the MESE receptor, compounds of formula I! are particularly suitable for the treatment of diseases associated with impaired regulation of angiogenesis, especially diseases caused by ocular revascularization, especially retinopathy such as diabetic retinopathy or age-related macular degeneration, psoriasis,

Hippel-Lindau, hemangioblastoma, angioma, mesangial proliferative cell disorders, such as chronic or acute kidney disease, for example, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes or transplant rejection, or especially inflammatory kidney disease, such as glomerulonephritis, especially mesangioproliferative glomerulonephritis, hemolytic-uremic syndrome, diabetic nephropathy, hypertensive nephrosclerosis, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, including rheumatoid arthritis, fibrotic disorders (for example, liver cirrhosis), diabetes, endometriosis, chronic asthma, arterial or post-transplant atherosclerosis, neurodegenerative disorders, for example, multiple sclerosis, and mainly tumor diseases, such as cancer (predominantly solid tumors, as well as leukemias), mainly such as breast cancer, adenocarcinoma, colorectal cancer, lung cancer (predominantly but non-small cell lung cancer, kidney cancer, liver cancer, pancreatic cancer, ovarian cancer or prostate cancer, as well as myeloma, mainly multiple myeloma, myelodysplastic syndrome, AML (acute myeloid leukemia), AMM (angiogenic myeloid metaplasia), mesothelioma, glioma and glioblastoma. The compounds of formula I, due to their activity as kinases, are also useful for treatment related to transplantation.

The following examples are intended to illustrate the present invention without limiting its scope.

GENERAL METHODS OF SYNTHESIS

Of course, compounds of formula (I) can be prepared according to the following schemes.

Scheme 1 ey -e ; S E-

BUT ost v u X YaAro KI Ch

Y uv 4 you o zha 5 y y - sho - I 'tch tanya I; And in a dream I: she sk and I Z-ya, bag Z Ya t, and Sha ee she ж ННШШ в. Academy of Sciences

E U vi Navoi, in vol

Kk and Z A Ag;

Y Z or NM -ShsV in:

Compounds such as 7 (in which EC: represents H or alkyl, Ka and Co represent substituted alkyl, H or, taken together to form heterocyclyl, Ag' represents substituted phenyl, heteroaryl, or heterocyclyl, K5 and Kee represent H or halogen, 22 represents M or CH), can be obtained according to the general method described in scheme 1. The combination of hydroxyindole 1 with containing functional groups pyrimidine or pyridine 2 (in which IS denotes a halogen, etc. or an activated alcohol) is carried out by treatment with a suitable base (such as DBU) in a solvent (such as acetonitrile) at RT or, preferably, by heating from RT to the boiling point to give 3. The formation of urea 7 can be carried out by various techniques such as treatment with a suitable base (such as Mann or

ITMR) in a solvent (such as DMF or THF) preferably at a temperature from 0 "C to RT, then isocyanate 4 or activated carbamate 5 (where Ag is phenyl or substituted phenyl) is added.

Alternatively, 7 can be prepared by pre-activating C or 6 with a coupling reagent (COS) such as CDI (1,1"-carbonylimidazole) and the like, followed by coupling with the other component, facilitated by a suitable base (such as EniZM, Man) .

Scheme of the 2nd century

And well set, 1, i. in M you and

M hu -kh nku yin. And aa X MN A y

Her І І ГТ 2nd, і В AB окавеМ о Me zro tyu

M re - yu TsN- - t or Y Z y | I. L, -i.

I v rak chn 2. Mas Ne ШЙ and dya v me: IN sel pr el K y UeshchN i o mia

Moi v: V. i KI 7 1 vi i Ki o v, Va Z At"

Compounds such as 10 (in which Ki, Ag»g, and Co and Ke are as described above, K.1 and Ki» are H or alkyl, and Kz and K:i» are H, alkyl, substituted alkyl , aryl, heteroaryl, heterocyclyl or, taken together to form heterocyclyl or heteroaryl and M denotes M or -5(02)-), are prepared by the general procedure described in Scheme 2. Compound 8 is formed by deprotection of the protecting group 7a by acid treatment (TPA , M5OH, etc.) followed by conversion of the obtained alcohol into a suitable IS (mesylate, halogen, etc.). Carbonyl va can be obtained by oxidation (using RDM, etc.) of the alcohol obtained above to give an aldehyde (K2-H) or by a sequence of reactions that includes oxidation to an aldehyde, followed by the addition of an alkyl group-retaining organometallic reagent (such as an alkyl group-retaining Grignard reagent) , followed by a second oxidation with the preparation of the corresponding keto-compound va (Kg - alkyl). Treatment of the nucleophile 9 with a suitable base (EizM, ManN, etc.) and 8 at a temperature from 0 "С to the boiling point in a suitable solvent gives 10. Alternatively, 10 can be obtained by the reaction of 9 under conditions of reductive amination (mMa(AsoO)zVN, etc.) with carbonyl you

Scheme Z

In, in

M. o M.O M. 0

MY OO

M. 2 Y M --e M | M nina a | M neck neck shi

AND

A, M B, (c) Ag, in M B, (c) Ag in M B, IF) Ag;

Wu t 11 Vo 12

Compounds such as 12 (in which K, Ar, and K5 and Ke are as described above, K0 and K2 are H, or alkyl, E0 is alkyl, acyl, or sulfonyl, and p is 0 or 1), obtained by the general method described in Scheme 3. Compound 11 is formed by removing the protecting group 765 (in which

Az denotes a suitable protecting group on the nitrogen atom, such as tert-butyl carbamate) by acid treatment (TPA, etc.). Then, the free amino group in 11 is alkylated, adylated or sulfonylated and compound 12 is obtained.

Scheme 4 stage C c. I. E and in Vych tr vot In her and E.e zi - and a shk i

BUT Saint May az t M, still yi rya A M you: we Va b DAT nn o MM new with M y 4 o 7 or Ж ; cha o i y

Ag Iv: and . or shchi and Ag. 5 A, or NYA, with St. De Hak

Compounds of type 15 (in which Ki, Agg, and K5 and Kei are defined as above, and Ki0 is alkyl, substituted alkyl, amide, carboxylic acid ester, or acid) are usually prepared as described in Scheme 4. Hydroxyindole Compound 1 with a pyrimidine or pyridine functional group retainer 13 (in which GO denotes a halogen, etc. or an activated alcohol and M denotes a halogen, alkyl, or carboxy group) is carried out by treatment with a suitable base (such as DBU, Mann, Maon, etc.) in a suitable solvent at RT or upon heating preferably from RT to the boiling temperature followed by the formation of urea, generally as described in Scheme 1, and 14 is obtained.

Additional U modification (such as reduction, amidation, hydrolysis, and coupling with an organometallic reagent) in compound 14 provides compounds of type 15.

The scope of this invention also includes any variant of the methods proposed in this invention, in which the intermediate product obtained at any of its stages is used as a starting substance for other stages, or in which the starting substances are formed under conditions of carrying out reactions , or in which the reaction components are used in the form of their salts or optically pure antipodes.

The compounds of the present invention and intermediates can also be converted into one another by well-known techniques.

In the case of groups of preferred compounds of formula I below in the present invention, the definitions of the substituents indicated in the general definitions above in the present invention can be used, for example, to replace one or more up to all of the more general definitions with more specific definitions or, especially, by definition, described as better.

Compounds of formula I are obtained by similar methods, which for other compounds, in principle, are known in this field of technology, but are new when used to obtain the compounds proposed in this invention, and are preferably obtained by methods described below in the "examples" section, or similar methods.

Propharmaceutical derivatives of the compounds proposed in this invention can be prepared by methods known to those of ordinary skill in the art (for additional details, see, for example, Zatsipieg ei a!., (1994), Viogdapis apa Meadisipa! Spetivigu I eNeg5 , Moi. 4, p. 1985).

For example, suitable prodrugs can be prepared by reacting a non-derivative compound of the present invention with a suitable carbamoylating reagent (eg, 1,1-acyloxyalkyl carbochloridate, p-nitrophenyl carbonate, etc.).

The protective group-containing derivatives of the compounds proposed in this invention can be prepared by methods known to those skilled in the art. A detailed description of the methods applicable to the introduction of protective groups and their removal is given in the publication of T. MU.

Steepe, "Rgoivsiipd Sgoyrz ip Ogdapis Spetivigu", Z'Ya eaiiop, dhopp Umieu apa 5opv, Ips., 1999. Suitable protecting groups can be introduced, used and removed at appropriate stages at any stage of obtaining a compound of formula Y.

The compounds of the present invention can be easily obtained or formed by the method of the present invention in the form of solvates (eg, hydrates). The hydrates of the compounds proposed in this invention can be easily obtained by recrystallization from a mixture of aqueous/organic solvents such as dioxane, tetrahydrofuran or methanol.

Intermediates and final products can be processed and/or purified by standard techniques, for example, using chromatographic techniques, partitioning techniques, (re-)crystallization, etc.

Abbreviations

ACN acetonitrile atm. atmosphere

ATP adenosine-5'-triphosphate

BOC tert-butylcarboxy group

BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate

God is wide

BSA bovine serum albumin a doublet

DBU 1,8-diazabicyclo|5.4. Fundec-7-en

ДЭ 1,2-dichloroethane aa doublet of doublets

DCM dichloromethane

DIPEA diisopropylethylamine

DMAP 4,4-dimethylaminopyridine

DME 1,4-dimethoxyethane

DMF M, M-dimethylformamide

Dess-Martin RDM reagent: 1,1,1-triacetoxy-1,1-dihydro-1,2-benzodioxol-3(1H)-one

DMSO dimethylsulfoxide

DT dithiothreitol

EDTC ethylenediaminetetraacetic acid

IER ionization by electrospray

EOAc ethyl acetate

KFC flash column chromatography g grams h. hours)

NATI O0-(7-azabenzotriazol-1-yl)-M, M, M'; M'-tetramethyluronium hexafluorophosphate

NVTII O-(benzotriazol-1-yl)-M, M, M'M'- tetramethyluronium hexafluorophosphate

NEW 1-hydroxy-7-azabenzotriazole

HPLC high-performance liquid chromatography

IR infrared spectroscopy

LCMS liquid chromatography and mass spectrometry

TMPL 2,2",6,6--tetramethylpiperidinlithium

M molar concentration t multiplet

Meon methanol waves. minute(s) ml milliliter(s) mmol millimole

MS mass spectrometry

M5OH methanesulfonic acid

MV microwave radiation t/2 ratio of mass to charge n. normal concentration

NMR nuclear magnetic resonance

Ra/C of palladium on coal freq./million parts per million

RUVOR benzotriazol-1-yloxytripyrrolidinephosphonium hexafluorophosphate racemic

CT room temperature

While holding a singlet

HRP supercritical liquid chromatography

It's a triplet

TVZSI tert-butyldimethylsilyl chloride

TFC trifluoroacetic acid

THF tetrahydrofuran

Example 1: 2-Methyl-1H-indol-5-ol.

N

M

-iX on

To a pre-cooled (0 "С) solution of 5-methoxy-2-methyl-1H-indole (5.0 g, 31.0 mmol) in 100 ml of DCM in an atmosphere of dry nitrogen is added VVgz (1 M solution, 46.5 The solution is then allowed to slowly warm to room temperature for 2 hours. The solution is then poured into water, neutralized to pH 7 with a saturated aqueous solution of sodium bicarbonate, and extracted using EOASc.

The extract is washed with saline, dried over sodium sulfate and concentrated to obtain 2-methyl-1H-indol-5-ol. MS (ER) t/2 148.2 (M-n1).

Example 2: 6-Fluoro-1H-indol-5-ol 2-A. 1-Benzyloxy-2-fluoro-3-methyl-4-nitrobenzene.

What - oh

E with

1,2-difluoro-3-methyl-4-nitrobenzene (12 g, 69 mmol, publication UUMO2007121416) is added to a suspension of potassium carbonate (19.2 g, 138 mmol) and benzyl alcohol (22 ml) and the mixture is heated at 180 " C for 2 h. Then the reaction mixture was diluted with EAs and washed with water. The organic layer was concentrated and the residue was purified by KFC (E(Ac/heptane from 0 to 2095) to give 1-benzyloxy-2-fluoro-3-methyl- 4-nitrobenzene. "H NMR (400 MHz, MeObr) b frequency/million 7.87 (da, 9U-9.35, 2.02 Hz, 1 H), 7.44-7.47 (t, 2 H), 7.32-7.41 (t, C H), 7.17 (1, U-8.72 Hz, 1 H), 5.26 (5, 2 H), 2.49 (a, U-2.78 Hz, Z H). 2-8. 4-Fluoro-1H-indol-5-ol.

N

M m on

IS

1-Benzyloxy-2-fluoro-3-methyl-4-nitrobenzene (5 g, 19 mmol) is dissolved in M,M-dimethylformamide dimethyl acetal (15 ml) and heated in a microwave reactor at 180 "C in a sealed vessel for 1 h. Then the solution was concentrated under reduced pressure. The resulting residue was dissolved in THF and Ra/C (1.0 g, 1095, 0.95 mmol) was added. The mixture was stirred under hydrogen at room temperature for 16 h and then filtered through a pad of celite and concentrated The residue is purified by KFC (EIOAc/heptane from 0 to 40 95) and 4-fluoro-1H-indol-5-ol (1.5 g, 52 95 yield) is obtained. MS (IR) t/72 152.1 (M--1); "H NMR (400 MHz, DMSO-av) b freq./million 11.02 (Bg. 5., 1 H), 8.79 (5, 1 H), 7.26 ( I, 9-2.78 Hz, 1 H), 7.00 (a, 9U-8.59 Hz, 1 H), 6.75 (I, U-8.46

Hz, 1 N), 6.34 (t, 1 N). 2-6. 6-Fluoro-1H-indole-5-ol. m E and on b6-Fluoro-1H-indol-5-ol are synthesized as described in publication M/O2003064413. MS (ER) t/2 152.1 (M-y1).

Example 3: 5-(2-("tert-butyldimethylsilaniloxy)-1,1-dimethylethyl|-2H-pyrazole-3-ylamine 3-A. Methyl ether of 3-(tert-butyldimethylsilaniloxy)-2,2-dimethylpropionic acid.

and / resia (in)

3-Hydroxy-2,2-dimethylpropionic acid methyl ester (5 g, 37.8 mmol), imidazole (3.86 g, 56.8 mmol), and 4-pyrrolidinepyridine (193 mg, 1.32 mmol) were combined in DCM (400 mL), then tert-butyldimethylsilyl chloride (6.84 g, 45.4 mmol) was added. Then the mixture is stirred at RT for 4 hours.

Then the mixture is partitioned between DCM and a saturated aqueous solution of Mansoz. The organic layer is separated, dried over anhydrous Mag250»4 and concentrated in vacuo. The residue is then purified by HPLC (from heptanes to E(OAc/heptanes 5:95)) and the product is obtained as an oil (6.4 g, 69 95). "H NMR (400 MHz, SOCI") b parts/million 3.63 (5, C H), 3.54 (5.2 H), 1.13 (5, 6 H) 0.85 (5.9 H), 0.00 (c, b H). 3 -B. 5-("tert-butyldimethylsilanyloxy)-4,4-dimethyl-3-oxopentannitrile and

I. / Oche

M

(in)

A solution of n-butyllithium (17.9 mL, 28.6 mmol, 1.6 M in heptane) is added to a pre-cooled (-78 "С) solution of diisopropylamine (4.26 mL, 29.9 mmol) and THF (45 mL ).After 30 min, a combination of 3-(tert-butyldimethylsilanyloxy)-2,2-dimethylpropionic acid methyl ether (3.2 g, 12.9 mmol) and acetonitrile (1.35 mL, 26 mmol) was added. warm to RT and then adjust the pH to 8 by adding 4 N HCl. The mixture is then partitioned between DCM and sat.

Mag5O", filtered and concentrated to obtain the desired compound. MS (IER) t/2 256.1 (M-n1). 3-6. 5-(-2-"tert-butyldimethylsilanyloxy)-1,1-dimethylethyl|-2H-pyrazole-3-ylamine. p: and

Ko) / Ku mn,

MAM

N

A solution of 5-(tert-butyldimethylsilanyloxy)-4,4-dimethyl-3-oxopentanenitrile (3.32 g, 12.9 mmol), hydrazine (0.62 g, 19.5 mmol), and Meon (50 mL) heated at 70 "C for 6 h. Then the solution is concentrated in vacuo and the residue is purified using KFC (50-100 95 EUAs/heptanes) and the desired compound is obtained. MS (ER) t/2 270.3 (M.n-1 ).

Example 4: Methyl ether of 4-methyltetrahydropyran-4-carboxylic acid. (c) then (c)

To a solution of diisopropylamine (10.2 ml, 72.8 mmol) in THF (400 ml) at -78 "С is added p-VIII (25.2 ml, 1.6 M in heptane). The reaction mixture is removed from the bath and stirred for 10 minutes. Then it was re-cooled to -78 "C and methyltetrahydro-2H-pyran-4-carboxylate (6.48 mL, 48.6 mmol) was added. In 30 minutes. iodomethane (6.07 mL, 97 mmol) was added and the reaction mixture was allowed to warm to RT. Then the reaction is stopped with 1 n. NSI (200 ml) and extracted with EOASc.

The organic layer is dried and evaporated to obtain 4-methyltetrahydropyran-4-carboxylic acid methyl ester. MS (IER) t/2 159.3 (M'H1).

Example 5: Tert-butyl ether of 3-(1-methylcyclopropyl)-5o-phenoxy-carbonylaminopyrazole-1-carboxylic acid 5-A. 3-(1-Methylcyclopropyl)-3-oxopropionitrile. court

M

(6)

A solution of n-butyllithium (18.1 mL, 28.9 mmol, 1.6 M in heptane) was added to a pre-cooled (-78 "С) solution of diisopropylamine (4.31 mL, 30.2 mmol) and THF (60 mL ).After 30 min, a combination of 1-methylcyclopropanecarboxylic acid methyl ester (1.5 g, 13.1 mmol) and acetonitrile (1.37 mL, 26.3 mmol) was added. The reaction mixture was allowed to warm to room temperature and the pH was adjusted to 8 by adding ASON. Then the mixture is concentrated and the desired compound is obtained. MS (IR) t/2 173.9 (M.n1). 5-8. 5-(1-Methylcyclopropyl)-2H-pyrazol-3-ylamine. or

MAM

N

A solution of 3-(1-methylcyclopropyl)-3-oxopropionitrile (1.0 g, 8.1 mmol), hydrazine (0.52 g, 16.2 mmol), and MeOH (40 mL) was heated at 70 °C for 6 h . The solution is then concentrated in vacuo and purified by semi-preparative HPLC (X-Vhydde C18; 10-100 95 ACN/HgO with the addition of 0.195 MNAOH) and the desired compound is obtained. Alternatively, the crude residue can be used in the next step without additional purification. MS ( ER) t/ 137.9 (M--1). 5-C. Tert-butyl ether of 5-amino-3-(1-methylcyclopropyl)-pyrazole-1-carboxylic acid.

The introduction of the protective group of the VOS is carried out as described in the publication Temaneadgop I eyegz 2003, 44, 4491.

Ku kn,

Where is MAM?

MS (ER) t/2 238.0 (M--1). 5-O0. 3-(1-Methylcyclopropyl)-5-phenoxycarbonyl-aminopyrazole-1-carboxylic acid tert-butyl ether. (F)

Uh-oh

OU-K

MAM and

To a solution of 5-amino-3-(1-methylcyclopropyl)-pyrazole-1-carboxylic acid tert-butyl ether (3.90 g, 16.4 mmol) and phenyl chloroformate (3.11 mL, 24.6 mmol) in DCM (150 mL) add 2,6-lutidine (5.74 mL, 49.3 mmol). After 18 hours the solution is diluted with DCM (100 ml) and washed with 1 M HCl (250 ml). Then the organic layer is dried (Mag50»4), filtered and concentrated to obtain the desired compound. MS (ER) t/2 358.0 (M.n1).

The following compounds are obtained by a similar method.

SH Structure/chemical name MS (ER) t/2 (M-1 (c)

Wow

OU-M

MAM N

5-Era 370.1 tert-butyl ether of 3-(1-methylcyclobutyl)-5-phenoxycarbonylaminopyrazole-1-carboxylic acid

SHY Structure/chemical name MS (ER) t/2 (M-1

F)

Uh-oh

SOU-M

М-М Н 5-Е Ж 344.3 tert-butyl ether of 3-isopropyl-o-phenoxycarbonyl-aminopyrazole-1-carboxylic acid (o) c)

In o

SOU-M

M-M N

B-a 400.2 a I tert-butyl ether of 3-(4-methyltetrahydropyran-4-yl)-5-phenoxycarbonylaminopyrazole-1-carboxylic acid (c)

Uh-oh

Ha;

M-N

M

5-НЖ 3422 tert-butyl ether of 3-cyclopropyl-5-phenoxycarbonyl-aminopyrazole-1-carboxylic acid

N

2-X o

М-М already in what about GU 246.2 phenyl ether of (1-isopropyl-1H-pyrazol-3-yl)y-carbamic acid

N va:

M- M )-9

B that o GU 260.2 phenyl ether (1-isopropyl-o-methyl-1H-pyrazol-3-yl)-carbamic acid

N

MAM vk o GU 232.2 Phenyl ether of (1,5-dimethyl-1H-pyrazol-3-yl)-carbamic acid

SHY Structure/chemical name MS (ER) t/2 (M-1 2-kh

MAM )-T9 v-I o GU 260.2 Phenyl ether (1-tert-butyl-1H-pyrazol-3-yl)y-carbamic acid va

М-М )-79 5-М that o GU 260.19 phenyl ether of (1-isopropyl-o-methyl-1H-pyrazol-3-yl)-carbamic acid

N

MM 5-M / o GU 258.2 phenyl ether (5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)- carbamic acid

Wow MAM o 5-0 / Id GU 286.2 phenyl ether (1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)- carbamic acid

N. Y

E Tu

House 9

BRIV c) g zob phenyl ether (5-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-yl|- carbamic acid

Huh. Mother of God or Id GU 00 phenyl ether (1-ethyl-5-trifluoromethyl-1H-pyrazol-3-yl)- carbamic acid

H so,

MAM yan o (and 286.3 phenyl ether (5-cyclopropyl-1-propyl-1H-pyrazol-3-yl)- carbamic acid

SH Structure/chemical name MS (ER) t/2 (M-1 lu

MAM 9) 8 | Id GU 272.2 phenyl ether (5-cyclopropyl-1-ethyl-1H-pyrazol-3-yl)-carbamic acid

Example 6: 6-A. 3-Isopropylisoxazole-5-ylamine. until

GF) -

N.M

A solution of hydroxylamine sulfate (1.72 g, 20.9 mmol) in water (4 mL) was added at RT to a solution of 5-methyl-3-oxohexanenitrile (2.38 g, 19.0 mmol) and sodium hydroxide (0.837 g, 20 .9 mmol) in water (10 ml). After adjusting the pH value of the mixture to 8.20 with 5 95 Mahon, it is heated at 100 "C for 1.5 h. Then, concentrated hydrochloric acid (1.73 ml, 17.1 mmol) is added to the reaction mixture, then heated at 100 "C for 15 minutes. After cooling, the pH value is adjusted to 11 with 30,956 Maon and the mixture is extracted with EOAc (3x). The organic extracts are dried over Mag505 and concentrated to give 5-isopropylisoxazole-3-ylamine. MS (ER) t/2 127.2 (M-y1).

The following compounds are obtained by a similar method.

SH Structure/chemical name MS (IER) t/2 (M-n1)

IS

"M

Go) and -- 179.3

NOM

3-(4-fluorophenyl)-isoxazol-5-ylamine "M

GF) and: 6-C - 161.2

N.M

Z-phenylisoxazole-5-ylamine

GF) and" - 139.2

N.M. 3-(1-methylcyclopropyl)-isoxazol-5-ylamine "M

GF) and 6-E - 167.5

N.M

C-cyclohexylisoxazol-5-ylamine

"M - 6-E and 141.5 (M-1)

N.M

Z-isobutylisoxazol-5-ylamine "M

Go) and" 6-a - 123.2 (M-1)

N.M

Z-cyclopropylisoxazol-5-ylamine "M (F) their 6-H -Shsh 139.2

NOM

Z-cyclobutylisoxazol-5-ylamine o a - 155.5

NOM

3-(2,2-dimethylpropyl)-isoxazol-5-ylamine

Example 7: 7-A. 5-Isopropylisoxazole-3-ylamine. m? x /

N.M

Mahon (4.95 g, 124 mmol) was added to a mixture of 4-methyl-3-oxopentannitrile (11 g, 99 mmol) and water (200 mL). After complete dissolution of the Mahon granules, add hydroxylamine sulfate (8.93 g, 109 mmol) and after 5 minutes measure the pH (pH 7-8). The reaction mixture is heated to 40 "C and stirred for 72 h. Then, HCl (13.0 ml, 158 mmol, 37 95) is added in one portion and the reaction mixture is heated at 50 "C for 2.5 h. The reaction mixture is removed from the oil bath and allowed to cool to RT. Then add Mahon's solution (30 95 in HgO) and get a solution with a pH of 11.

Then EOAcC is added and the layers are separated. The aqueous layer is extracted with EOAcC (3x) until no more product is detected in the aqueous layer by LCMS. The combined organics are dried (Ma»5 O54 ) and evaporated to give 5-isopropylisoxazole-3-ylamine. MS (ER) t/ 127.2 (M-n1).

The following compounds are obtained by a similar method. 77711111 Structure/chemical name.ъ7//-:/ | MS (ER) pus (My mo x 7-8 151.2 (M-1)

NOM

5-(1-methylcyclopropyl)-isoxazole-3-ylamine m? 7-s x y 155.5 nom 5-(2,2-dimethylpropyl)-isoxazole-3-ylamine

AI Structure/chemical name of MS (IER). t/» (M-n1) ke o

M

7-0 M 183.2

N.M 5-(4-methyltetrahydropyran-4-yl)-isoxazol-3-ylamine de)

M

7-E at 139.2

N.M

B-cyclobutylisoxazole-Z3-ylamine de)

M

7-E at 167.5

N.M. 5-cyclohexylisoxazol-3-ylamine m? 7-6 and 125.2 nem 5-cyclopropylisoxazol-3-ylamine m? 7-H x 141.5 (MA)

N.M. 5-isobutylisoxazol-3-ylamine ke o

M

7-1 M 169.3

N.M. 5-(tetrahydropyran-4-yl)-isoxazol-3-ylamine

E mo E 7-4 x/ E 209.1

NOM

5-(3,3,3-trifluoro-1,1-dimethylpropyl)-isoxazol-3-ylamine

Example 8: 8-A. 5-Phenylisoxazole-3-ylamine. mo x and nom

Hydroxylamine sulfate (2.5 g, 30.3 mmol) is added with stirring to a solution of 3-oxo-3-phenylpropanenitrile (4 g, 27.6 mmol) and Mahon (1.27 g, 31.7 mmol) in a mixture of HgO ( 25 ml (25 ml).

The mixture is stirred at RT and then heated at 80°C for 22 h. Concentrated NOSI (3.39 mL, 41.3 mmol) is then added and the mixture is heated at 80°C for another 2 h. Then it is alkalized to pH 10 and extracted with EtOAc to obtain 5-phenylisoxazol-33-ylamine. MS (IER) t/ 161.2 (M-n1).

The following compound is obtained by a similar method. 8-8. 5-(4-Fluorophenyl)-isoxazol-3-ylamine

E mo x and nom

MS (ER) t/2 179.3 (M--1).

Example 9: 3-("tert-butyldimethylsilanyloxymethyl)-5-trifluoromethyl-phenylamine.

OtTV5

N.M | SE,

To a solution of 3-amino-5o-trifluoromethylbenzoic acid (2.0 g, 9.76 mmol) in THF (40 mL) at 0" was added HIAINa in THF (1 M, 39 mL). The mixture was refluxed and stirred for 62 h. Then the mixture was cooled to 0 "C and added Mac (2.2 g), then HgO (3.8 ml).

The suspension is stirred for 10 minutes. and then it is allowed to warm up to RT and stirred for another 40 min. The mixture was filtered and the solid was washed with EAs and Meon. The filtrate was concentrated, and the crude residue was mixed with imidazole (2.66 g, 39 mmol) and DCM (30 mL) at 0°C. TSS (3.5 g, 23.4 mmol) was added and the mixture was stirred at RT for 5 h. Then the reaction mixture is diluted with EtAs, washed with a saturated aqueous solution of Manso»z, saline solution and dried over Mag25O5. Concentration provides the desired compound, which is used in the next stage without additional purification. MS (IER) t/2 306.1 (M .-1).

Example 10: 5-Trifluoromethylpyridin-3-ylamine.

CE, there are xx and M

NOM

A mixture of 2-chloro-5-nitro-3-trifluoromethylpyridine (30 mg, 0.13 mmol), 10956 Ra/C (3 mg, 10 95 w/w), and MeOnH (5 mL) was stirred under hydrogen pressure, equal to 1 atm., during 3 h. Then the mixture is filtered through celite? and concentrated in vacuo to obtain the desired compound as an oil. MS (ER) t/2 162.9 (M--1).

Example 11: 3-Amino-M-isopropyl-5-trifluoromethyl)benzamide. what;

Se nm -

To a solution of 3-amino-5-(trifluoromethyl)benzoic acid (0.25 g, 1.22 mmol) in DMF (3 ml) is added

NOVI (0.494 g, 3.66 mmol), then NATIi (0.695 g, 1.83 mmol), propan-2-amine (0.311 mL, 3.66 mmol) and

DIPEA (0.96 ml, 5.48 mmol). After stirring at RT overnight, the solution is concentrated and the residue is dissolved in EIOAc, washed with a saturated aqueous solution of Mansoz, saline and dried over Ma»5Ox. After concentration, the residue is used at the next stage without additional purification. MS (ER) t/2 247.1 (M.n1).

Example 12: 3-Amino-5-trifluoromethylbenzonitrile.

MH,

IS

IS

To a solution of 3-nitro-5-(trifluoromethyl)benzonitrile (500 mg, 2.31 mmol) and acetic acid (6.62 mL, 116 mmol) in EN (10 mL) and water (10 mL) was added stannous chloride ( 2.61 g, 11.6 mmol) and the reaction mixture is heated at 80 °C for 2 h. The solvent is removed in vacuo and then the residue is partitioned between DCM and 4 N solution of NS. The organic layer is separated and then dried over anhydrous Mag5O» , filtered and concentrated.The residue was then purified using

KFC (100-100 956 E(OAc/heptane)) and the compound is obtained as a yellow oil (213 mg, 49 9b). MS (ER) t/2 185.3 (M--1).

Example 13 13-A. Phenyl ether of (5-trifluoromethylpyridin-3-yl)-carbamic acid.

SE. pogo f

OHM

N

The compound of example 7-A, 5-trifluoromethylpyridin-3-ylamine (385 mg, 2.37 mmol), was transferred to THF (25 mL) and at 0 °C pyridine (0.38 mL, 4.75 mmol) was added, then phenyl chloroformate (558 mg, 3.56 mmol). After 2 h, the reaction mixture was diluted with DCM (50 mL) and washed with water (50 mL). The organic layer was separated, dried over anhydrous Mg 5 O 4 , filtered, and concentrated.

Then the residue is purified by means of KFC (from EAs/heptanes 1:9 to EAs/heptanes 1:1) and the desired compound is obtained. MS (ER) t/2 283.0 (M.n1).

The following compounds are obtained by a similar method. structure/chemical name M -1

ES o ba 13-V X 367

Nn Nn phenyl-3-(isopropylcarbamoyl)-5-(trifluoromethyl)-phenylcarbamate

SE,

SU

- ОтТв5 13-С ohm 426.1

H phenyl-3-((tert-butyldimethylsilyloxy)methyl)-5-(trifluoromethyl)phenylcarbamate

HF) ty6y- 13-0 AH -0 247.3 o CM M

H phenyl ether (5-isopropylisoxazol-3-yl-carbamic acid

GF) 60-18-E D to 281.2 o SMM

H phenyl ether (5-tert-butylisoxazol-3-yl-carbamic acid

XA nm at 13-E at 305.0

Uh...

E M

E phenyl ether (3-cyano-5-trifluoromethylphenyl)-carbamic acid p. MS (ER) t/2

Structure/chemical name Ma (c) 13-6 S re pe 261.2 o cm o

H phenyl ether (3-tert-butylisoxazol-5-yl-carbamic acid 13-H (c)-8-O 281.2

J o o cm m

H phenyl ether (5-phenylisoxazol-3-yl-carbamic acid

IS

13th o'clock - 299.1

DZ o o TM m

H phenyl ether (5-(4-fluorophenyl)-isoxazol-3-yl|-carbamic acid) with 13-U, 259.2 units M

N-phenyl ether |5-(1-methylcyclopropyl)-isoxazol-3-yl|-carbamic acid

From to 13-K -. 275.2 o CM M

H phenyl ether (5-(2,2-dimethylpropyl)-isoxazole-3-yl|-carbamic acid

IF) -t30O- 15-I 261 and Fi Z re 51.3 o CM M

N phenyl ether of (5-isobutylisoxazol-3-yl)-carbamic acid - o -O- lev di ve om M

H phenyl ether of 5-cyclobutylisoxazol-3-yl)y-carbamic acid p. MS (ER) t/2

Structure/chemical name Ma 13-M g 245.2

Ха оди M

H phenyl ether of 5-cyclopropylisoxazol-3-yl)-carbamic acid

EC

С 0 13-О 339.1 ok M--

Нн Нн phenyl-3-(methylcarbamoyl)-5-(trifluoromethyl)-phenylcarbamate

And (in) them

OA Tk ve om o

N-phenyl ether of 3-cyclobutylisoxazol-5-yl)y-carbamic acid (c) 13-00 C re pe 261.2 o cm o

H phenyl ether (3-tert-butylisoxazol-5-yl-carbamic acid 13-8 (c) of them 281.2

Ho om Mk s,

H phenyl ether of (3-phenylisoxazol-5-yl)-carbamic acid

IS

13-5 at 4,299.1

Hom o cm o

H phenyl ether of 3-(4-fluorophenyl)-isoxazol-5-yl|-carbamic acid (c) and their 13-T АХ M 259.2 ом о

H phenyl ether of 3-(1-methylcyclopropyl)-isoxazol-5-yl|-carbamic acid p. MS (ER) t/2

Structure/chemical name Mi (c) their 13th DL m 275.2 o cm o

N phenyl ether of 3-(2,2-dimethylpropyl)-isoxazol-5-yl|-carbamic acid o cm o

N phenyl ether of 3-isobutylisoxazol-5-yl)-carbamic acid 13-Mu FI ii g 247.3 o cm o

H phenyl ether of 3-isopropylisoxazol-5-yl)-carbamic acid (c) their вх СХ and раве о см о

N-phenyl ether of (Z-cyclopropylisoxazol-5-yl)-carbamic acid () 13-h vot 303.2

HoAue about SM M

H phenyl ether of 5-(4-methyltetrahydropyran-4-yl)-isoxazol-3-yl|- carbamic acid 13-27 (c) -8-O 287.2

Kha o SMm M

H phenyl ether of 5-cyclohexylisoxazol-3-yl)-carbamic acid () 13-AA (c) -8-O 289.2

Zhd o o SMm M

H phenyl ether of 5-(tetrahydropyran-4-yl)-isoxazol-3-yl|-carbamine c c. MS (ER) t/2 structure/chemical name Ma p TT: UNO KO 13-AB ) of them 287.2

ХК од ШК)

N-phenyl ether of 3-cyclohexylisoxazol-5-yl)-carbamic acid 13-AS sec 219.2 o TMm M

H phenyl ether of 5-methylisoxazol-3-yl-carbamic acid

E about

ME

13-Ar Xm 329.0 o n 5-(3,3,3-trifluoro-1,1-dimethyl-propyl))-isoxazol-3-ylcarbamic acid phenyl ether

Example 14 14-A. 5-(6-Benzyloxymethylpyrimidin-4-yloxy)-1H-indole.

M F) two; and M

N

Co

DBU was added to a solution of 5-hydroxyindole (1.33 g, 10 mmol) and 4-benzyloxymethyl-b-chloropyrimidine (2.35 g, 10 mmol) in acetonitrile (20 mL). After 16 hours in CT, the solution is concentrated under reduced pressure. The residue is purified using KFC (E(OAc/heptane from 0 95 to 40 95) and 5-(6-benzyloxymethylpyrimidin-4-yloxy)-1H-indole is obtained. MS (IER) t/2 447.0 (M. n1).

The following compounds are obtained by a similar method. 14-8. 5-(6-Benzyloxymethylpyrimidin-4-yloxy)-4-fluoro-2-methyl-1H-indole.

Eh ke)

StSo- 4 M

N

That's it

MS (ER) t/2 364.0 (M-n1) 14-60. 5-(6-Benzyloxymethylpyrimidin-4-yloxy)-4-fluoro-1H-indole.

IS

I love it

Hundred -4 M

N o

MS (ER) t/2 350.2 (M-n1)

Example 15 15-A. (4-Fluoro-3-trifluoromethylphenyl)-amide of 5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid.

M. I. and E

Sstso - i

M

FD, on

n-butyllithium (2.5 M in hexane, 2.9 ml) is added to a solution of 2,2,6,6-tetramethylpiperidine (1.07 g, 7.6 mmol) in THF (40 ml) at -78 "С , then 5-(b-benzyloxymethylpyrimidin-4-yloxy)-1H-indole (2.4 g, 7.3 mmol), maintaining the temperature below -70 "С. The reaction mixture was stirred for 10 min., then 1-fluoro-4-isocyanato-2-trifluoromethylbenzene (1.56 g, 7.6 mmol) was added and the solution was then allowed to slowly warm to RT and stirred for another 16 h. The solvent is then removed under reduced pressure and the residue partitioned between EIAs and water. The organic layer is separated, dried and concentrated. Then the residue is purified by means of KFC (EIOAc/heptane from 0 90 to 100 Ob) and the desired compound is obtained. MS (ER) t/2 537.0 (M.n1).

The following compounds are obtained by a similar method.

Structure/chemical name MS PER) t/2 (М.Н1

M, o) Rzs ov; dp and 15-8 M 519.2

DI

5-(6b-benzyloxymethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide

M. o

OO

--

M M I

X-m (2-fluoro-3-trifluoromethylphenyl)-amide of 5-(6-benzyloxy-methylpyrimidin-4-yloxy)-indole-1-carboxylic acid

Me oh go

(2-fluoro-5-trifluoromethylphenyl)-amide of 5-(b-benzyloxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid

IS

Мо ЕС и и и де и 15-Е 551.0

M z

DI

5-(6-benzyloxymethylpyrimidin-4-yloxy)-4-fluoro-2-methylindole-1-carboxylic acid (3-trifluoromethylphenyl)-amide

IS

M o me;

CD of their building and 15-E 537.0

5-(6b-benzyloxymethylpyrimidin-4-yloxy)-4-fluoroindole-1-carboxylic acid (3-trifluoromethylphenyl)-amide

Example 16 16-A. (4-Fluoro-3-trifluoromethylphenyl)-amide of 5-(6-hydroxymethylpyrimidin-4-yloxy)-indole-1-carboxylic acid.

Mao E vv;

H-m he he

A solution of 5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (4-fluoro-3-trifluoromethylphenyl)-amide (2.0 g, 3.7 mmol) in TFC (20 ml) is heated at 60 "C for 24 h and then allowed to cool to RT. The solution is then poured into 100 g of crushed ice. The oily product is separated and then purified by HPLC (EIOAc/heptane from 095 to 100 95) and the desired compound is obtained. MS ( ER) t/2 447.0 (M--1); "H NMR (400 MHz, DMSO-α) b freq./million 10.40 (5.1 H), 8.65 (y, 9-1 .01 Hu, 1 H), 8.29 (a, U-9.09 Hz, 1 H), 8.09 - 8.12 (t, 2H), 8.99-8.04 (t, 1 H ), 7.58 (i, 9-9.60 Hz, 1 H), 7.51 (a, 9-2.53 Hz, 1 H), 7.16 (da, 9U-8.84, 2, 53 Hz, 1 H), 6.99 (a, 9U-1.01 Hz, 1 H), 6.82 (a, 9-3.79 Gu, 1 H), 5.61 (I, 9U-5 .05 Hz, 1 N), 4.52 (a, U-5.05 Hz, 2 N).

The following compounds are obtained by a similar method. with. MS (ER) 1

NMR structure/chemical name H' NMR (400 MHz)

Mo); X (meOb) 5 parts/million 8.61 (y, 9U-1.01 Hz, y 1 H), 8.37 (a, Y-8.84 Hz, 1 H), 8.07 (5, 1

Mo M SE. | H), 7.96 (a, 9U-3.79 Hz, 1 H), 7.90 (aa, 16-V Khm Z |y-7.96, 1.39 Gu, 1 H), 7.58 (i, 9U-7,96 Gu, 429 4

He o nn 1 H), 7.45 (5.1 H), 7.43 (a, 9-2.27 Hz, 1 "(3-trifluoromethylphenyl)-amide 5-(6- M), 7.13 (ai . 79 Hu, 1 indole-1-carboxylic acid H), 4.63 (5.2 H).

Mo); Х (DMSO-ав) b parts/million 10.28 (5, 1 N), и 8.65 (a, 9U-1.01 Gu, 1 N), 8.27 (a, 9U-8.84

Mo M SE. | Hz, 1 N), 8.11 (a, 9-3.79 Hz, 1 N), 7.92 - r with 17.96 (t, 1 N), 7.68 - 7.73 (t, 1 H), 7.47 16-С ME 466.9

OH o nn -7.52 (t, 2 H), 7.16 (da, 9U-8.97, 2.40 (2-fluoro-3-trifluoromethylphenyl)-amide | GU; 1 H), 6.98 (y, 91.01 Hz, 1 H), 6.83 5-(6-hydroxymethyl-pyrimidine-4- (a, y-8,t9 Hu, 1 NU, 5.60 - 5.62 (t, 1 H), yloxy)-indole-1-carboxylic acid 4.52 (j, 955.81 Gu, 2 H).

E.S (DMSO-av) b frequency/million 10.27 (5.1 N),

M. 0 Z 8.65 (y, 9-1.01 Hz, 1 N), 8.27 (a, 9-8.84 that IF; o Hz, 1 NU), 8.10 (a, 9U -3.79 Hz, 1 N), 8.05

Mo 2 M (ai, 9U-6.95, 2.15 Hz, 1 H), 7.72 (a, y-4.04 Hz, 1 H), 7.62 (Her, Y-9.35 Hz . 40 Hz, 1 H), 6.98 (a, y-1.01 or-o-trifluoromethylphenyl)-amide gu 4 n), 6.82 (y, 9-3.79 Hz, 1 H), 5, 61 5-(6-tihydroxymethyl-pyrimidine-4-(6 94-5.68 Hz, 1 H), 4.52 (y, 925.31 Hz, 2 yloxy)-indole-1-carboxylic acid H

IS

EC

M i); (DMSO-av) b freq./million 10.49 (5.1 N),

Ty Z 8.65 (5, 1 H), 8.08 - 8.19 (t, Z H), 7.97

M. and M (y, 9-8.59 Hz, 1 H), 7.66 (I, 9U-8.08 Hz, 1 16-E rya NU, 7.52 (a, 9U-7.83 Hz , 1 H), 7.27 - 7.34 447.0

OH o nn (t, 1 H), 7.17 (c, 1 H), 6.94 (a, 20-3.54 4-fluoro-(3-trifluoromethylphenyl)-amide Hz, 1 H), 5, 68 (bg. 5, 1H) 4.57 (5, 2 H). 5-(6-hydroxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid

Example 17 17-A. (3-Trifluoromethylphenyl)-amide of 4-fluoro-5-(6-hydroxymethylpyrimidin-4-yloxy)-2-methylindole-1-carboxylic acid.

EU

Mag Z ps o

M M

H-k he he

A solution of (3-trifluoromethylphenyl)-amide of 5-(6-benzyloxymethylpyrimidin-4-yloxy)-4-fluoro-2-methylindole-1-carboxylic acid (2.0 g, 3.6 mmol) and M5OH (15 ml) is heated at 100 "C for 8 min. and then poured into a saturated aqueous solution of ManHsSoO»z. The aqueous phase is extracted with EtOAc. The organic phase is washed with saline solution, dried over anhydrous Ma5O" and purified using KFC (from EIOAc/heptanes 2:8 to EIOAcS) and obtain the desired compound. MS (IER) t/2 461.1 (M--1); "H NMR (400 MHz, DMSO-α) 6 ppm 11.00 (5.1 N) , 8.61 - 8.65 (t, 1 N), 8.12 (5.1

NU, 7.91 (5, 1 N), 7.66 (1, 9U-7.71 Gu, 1 N), 7.52 (y, 9-8.84 Hz, 1 N), 7.12 - 7.22 (t, 2 H), 6.84 (Br. 5., 1 H), 6.63 (5, 1 H), 5.66 (I, U-5.94 Hz, 1 H), 4.56 (a, 9U-5.56 Hz, 2 H), 2.59 (5, C H).

The following compound is obtained by a similar method. 17-8. 16-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-yl|-methanol

IS

Mag c) So"

M M

N on

MS (ER) t/2 274.2 (M-n1).

Example 18 18-A.. (4-Fluoro-3-trifluoromethylphenyl)-amide of 5-(b-methanesulfonylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid.

Mag E vav; o J-m o 7 IF) H te c)

To a solution of 5-(6-hydroxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (4-fluoro-3-trifluoromethylphenyl)-amide (260 mg, 0.6 mmol), methanesulfonic anhydride (240 mg, 1.4 mmol) and

To THF (15 mL) was added pyridine (0.2 mL). The mixture is stirred at RT for 0.5 h. and then filtered. The filtrate is used in the next stage without purification. MS (IER) t/2 525.0 (M--1).

The following compounds are obtained by a similar method. with o. MS (ER) t/2 structure/chemical name Ma (6)

Se If; IN

M. 22 M

In SE, 18-8 0-9 o and 507.0 tv. (6) (3-trifluoromethylphenyl)-amide of 5-(b-methanesulfonylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (6) shk;

MO M

What That 18-С ob o Y 524.8 vk, (6) (2-fluoro-3-trifluoromethylphenyl)-amide of 5-(6b-methanesulfonyl-methylpyrimidin-4-yloxy)-indole-1-carboxylic acid

E.S

Ge) With higher education;

M. 2 U. - M 18-0 about 524.8 ra (c) (2-fluoro-5-trifluoromethylphenyl)-amide of 5-(6b-methanesulfonyl-methylpyrimidin-4-yloxy)-indole-1-carboxylic acid

E o) o) Z

There are SOo-

M. 22 M 18-E o rya 538.8 od that (v; H rec (v) 6-(4-fluoro-2-methyl-1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|- Pyrimidin-4-yl methyl ester of methanesulfonic acid

IS

(6)

With SO

M. 2 M 18-E o 352.0 o what in-- (6) 6-(4-fluoro-2-methyl-1 H-indol-5-yloxy)-pyrimidin-4-ylmethyl ether of methanesulfonic acid o. MS (ER) t/2

Structure/chemical name Mch

And Es

Mao and

SUS

M. 2 U. - M in-- (c) 6-(4-fluoro-1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyrimidin-4-ylmethyl ether of methanesulfonic acid

Example 19 19-A. (4-Fluoro-3-trifluoromethylphenyl)-amide of 5-(b-methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid.

Mat E va;

МХ SEZ

M tn o n

Methylamine ( 1 ml, 2.0

M in methanol). The mixture was stirred at room temperature for 16 h, then concentrated under reduced pressure. The residue is diluted with EtOAc and washed with water and saline. The organic layer is separated, dried and concentrated. Then the residue is purified by KFC (Meon with the addition of 1 95 MNAOH/DHM from 0 to 10 95) and the desired compound is obtained.

MS (ER) t/2 460.1 (M-e-1); "H NMR (400 MHz, MeOb) b frequency/million 8.65 (a, 9U-1.01 Hz, 1 H), 8.35 (a, U-8.84

Hz, 1 H), 8.04 (aa, 9U-6.19, 2.65 Hz, 1 H), 7.90 - 7.94 (t, 2 H), 7.41 (a, 929-227 Gu, 1 H), 7.35 (I, U-9.60 Hz, 1

H), 7.11 (aa, 9-8.97, 2.40 Hz, 1 H), 7.00 (5, 1 H), 6.74 (a, 9U-3.79 Hz, 1 H) , 3.82 (5, 2 H), 2.43 (5, C H).

The following compounds are obtained by a similar method using as starting substances the compounds of example 18 A-(a.s. MS (ER) 1

OO Structure/chemical name NMR (400 MHz)

Mu o X (meob) 5 parts/million 8.64 (5, 1 H), (y 8.34 (a, 9U-9.09 Hz, 1 H), 8.05 (5,

M. 2 M SE. 1 H), 7.93 (y, 9-3.79 Hz, 1 H), p 7.89 (a, Y-8.08 Hz, 1 H), 7.56 (y, 19-8 МН o nH 9U-7.96 Hz, 1 N), 7.40 -7.46(t,2 | 4421

H), 7.10 (da, 9U-8.97, 2.40 Gu, 1 (3-trifluoromethylphenyl)-amide 5-(6-p), va 50. ac base methylaminomethylpyrimidin-4-yloxy)- Nu ) , 3.17 (in, ), 2.40 (5, indole-1-carboxylic acid).

We x E (MeOb) b frequency/million 8.65 (4,

TY 3-1.01 Hu, 1 H), 8.36 (a, U-8.84

M. 2 M SE Hu, 1 H), 8.05 (aa, U-6.19, 2.91

Khm З Hz, 1 H), 7.91 - 7.95 (t, 2 H), 19-С МН o НН 7.42 (a, 9-2.27 Hz, 1 H), 7.36 (i , 488.0

A 3-9.60 Hz, 1 H), 7.12 (yes, U-8.84, " 2.53 Hz, 1 H), 7.03 (5, 1 H), 6.75 (4- fluoro-3-trifluoromethylphenyl)-amide 5-(6- (a, U-3.79 Hu, 1 H), 3.85 (5, 2 H), (isopropylaminomethyl)-pyrimidin-4-yloxy)- | 283 (t, 1 NU, 1.10 (a, U-6.32 Gu, indole-1-carboxylic acid. 6 H).

SG today 01 nyayuoyue Ter,

M o E (meob) 6 parts/million 8.64 (a, pe X 9-1.01 Gu, 1 H), 8.35 (4.9-9.09

M i M s Hz, 1 N), 8.04 (yes, 9-6.32, 2.78

Huh. Sez I | Hz, 1 H), 7.92 (a, 9-3.79 Hz, 1 M),

M 7.90 - 7.94 (t, 1 H), 7.41 (a, 19-0 МН o n 9-2.27 Hz, 1 H), 7.35 (i, 9-9.60 504 ,0 ed Gu, 1 NU, 7.11 (yes, 9-8.97, 2.40

Hz, 1 H), 7.02 (a, 9-1.01 Hz, 1 H), (4-fluoro-3Z-trifluoromethylphenyl)-amide 5-(6- | 6.74 (4, 9-3, 79 Hz, 1 N), 3.85 (5,

Deg-methoxyethylamino)-methyl|-pyrimidine-4-| 2 H), 3.47 - 3.51 (t, 2 H), 3.32 yloxy)-indole-1-carboxylic acid. 5, ZN), 2.76 - 2.79 (t, 2 H).

M. 0 (meobr) 5 parts/million 8.62 (y, also IF; 9-1.01 Gu, 1 H), 8.34 (4. 9-8.84

M. M SE HC, 1 H), 8.05 (with, 1 H), 7.93 (a, as with 9-3.54 Hz, 1 H), 7.89 (a, 9-8.08

Hz, 1 N), 7.56 (i, 9-8.21 Hz, 1 N), 19-E U on 7.40 - 7.45 (t, 2 N), 7.09 (5, 1 498 ,0

H), 7.02 (in, 1 H), 6.73 (a, 9-3.79 (3-trifluoromethylphenyl)-amide 5-(6-Gu, 1 H), 3.65 (rg. 5. , 1 H), 3.67 morpholin-4-ylmethylpyrimidin-4-yloxy)-(9, t, 4 H), 3.58 (5, 2 H), 2.50 (a, indole-1-carboxylic acid t, 4 H).

There are also; (MeOb) 5 ppm 8.64 (5.1 N),

And 8.35 (y, U-8.84 HZ, 1 H), 8.06 (5,

M. M C 1 NU, 7.94 (d, 9-3.54 Hz, 1 N), in Khm and 7.90 (4, 9-8.08 Hz, 1 N), 7.57 (i, 19-E M o nn 9-7.96 Hz, 1 H), 7.42 (y, 9-2.53 ABY

Hz, 2 H), 7.11 (yes, 9-8.84, 2.27 (3-trifluoromethylphenyl)-amide 5-(6- in CH What is dimethylaminomethylpyrimidin-4-yloxy)- 2 29 (in ) t ' ' indole-1-carboxylic acid Y Y " g schi X y (MeO0) b part./million 8.63 (a,

I p 9-1.01 Gu, 1 H), 8.36 (9, 9-8.84

M M SE Hz, 1 H), 8.05 (yes, 9-6.32, 2.78

X-m Hz, 1 NU, 7.94 (y, 9-3.79 Hz, 1 N), 19-65 m on 7.91 -- 7.95 (t, 1 N), 7.43 (4 , 516.0

Co y-2.27 HC, 1 H), 7.36 (i, 9-9.47

Hz, 1 H), 7,10-714(t,2 H (4-fluoro-3-trifluoromethylphenyl)-amide 5-(6-615 eto Hz, 1 no) - 4 N) 3.81 (5, 2 N), 2.52 (t, 4 MN). indole-1-carboxylic acid

Mao x (MeOb) b parts/million 8.64 (5.1 N),

That is IF; 8.35 (4, 9-9.09 Hz, 1 N), 8.06 (5,

M. M SE 1 NU, 7.94 (d, 9-3.54 Hz, 1 H), re with 7.89 (4, 9-8.08 Hz, 1 H), 7.56 (Y, 19 -Н МН о НН 3-8.08 Hz, 1 Н), 7.40 -746(T2 704 ра Н), 7.10 (44, 9-8.84, 2.27 Hz, 1

H), 7.02 (c, 1 H), 6.74 (a, 9-3.79 (3-trifluoromethylphenyl)-amide 5-(6- Hz, 1 NU, 3.82 (5, 2 H) . ).

about styuyunnnyanya | nyayueskyumo OrETEV, hai schi X (MeOb) 5 parts/million 8.62 (a,

I p 9-1.01 Hz, 1 N), 8.34 (4.9-8.84

M M SE Hz, 1 N), 8.05 (5, 1 N), 7.93 (a,

X-m 9-3.54 Hz, 1 N), 7.89 (4, 9-8.08 19-I m on Hz, 1 N), 7.56 4, 98.21 Hz, 1), | 498.0

C, about 7.40 - 7.45 (t, 2 H), 7.09 (5, 1 (3-trifluoromethylphenyl)-amide 5-(6- (i. about H; from the morpholine-4- ylmethylpyrimidin-4-yloxy)- (5.2 n) 2 BO (and so. 4 n). shk of indole-1-carboxylic acid I 7 SH

Mao x (MeOb) b freq./million 8.63 (4,

That is IF; 9-1.01 Gu, 1 H), 8.34 (4, 9-8.84

M. 2 M SE Hz, 1 H), 8.05 (5, 1 H, ) 7.93 (y, cancer 3 193.79 Hz, 1 H), 7.89 (y, 9-8.34 198 -/ MH o NN hz, 1 Well, 7.56 (,U-VO8 HZ, u850 o. 7.40 - 7.45 (t, 2 H), 7.10 (aa, i y 9-8.97 , 2.40 Hz, 1 H), 7.01 (5, 1 (Z-trifluoromethylphenyl)-amide 5-(6-(2- H), 6.73 (a, U-3.79 Hz, 1 H ), 3.84 methoxyethylamino)-methyl|-pyrimidine-4- (5.2 H), 3.47 - 3.50 (t, 2 H), yloxy)-indole-1-carboxylic acid 3.31 (5 , ZN), 2.75 -2.79 (t, 2 N).

M Go) (meob) 6 parts/million 8.64 (a, and If; 9-1.01 Hz, 1 H), 8.36 (a, 4-8.84

M. is M also Hz, 1 N), 8.06 (5, 1 N), 7.95 (a,

Mk Z U-3.79 Hz, 1 N), 7.90 (a, 9-8.34

Hz, 1 H), 7.57 (i, 9-7.96 Hz, 1 H), 19-K DU, OH 7.43 (9.94-2.27 Hz, 2 H), 7.12 ( 449, 7520 9-8.84, 2.27 HC, 1 H), 7.05 (5, 1 (3-trifluoromethylphenyl)-amide 5-(6- H), 6.75 (a, 9-3, 79 Hz, 1 H), 3.74 pyrrolidin-1-ylmethylpyrimidin-4-yloxy)- |(b5.2 H), 2.61 (t, 4 H), 1.81 (t, 4 indol-1- carboxylic acid H).

M o (Meob) 5 parts/million 8.64 (a, "ve X 9-1.01 Hz, 1 H), 8.35 (4.9U-8.84

M I IF; Hz, 1 N), 8.06 (5, 1 N), 7.94 (y,

SEZ y-3.79 Hu, 1 N), 7.89 (a, U-8.08 r Hz, 1 N), 7.56 (I, 9-7.96 Hz, 1 N),

MH o nH 7.40 - 7.45 (t, 2 H), 7.10 (da, y-8.97, 2.40 Hz, 1 H), 7.03 (5, 1 191 (Z nu, 6.74 (a, 9-3.79 Hz, 1 H), 3.92 |..2120 o (aaa, 9u-11.87, 4.04, 2.02 Hz, 2 , , H), 3 .86 (5, 2 H), 3.38 (9, (Z-trifluoromethylphenyl)-amide 5-16- 9-11 .75, 2.02 Gu, 2 H), 2.69 (y, (Ktetrahydropyran- 4-ylamino)-methyl-Y-10.74, 4.04 Hz, 1 H), 1.83 (aa, pyrimidine-4-yloxy)-indole-1-carboxylic acid Y-12.63, 4.04, 2.02 Hz, 2 N), 1.35 acid -145(t.2 N). (MeOb) b parts/million 864 (5.1 N), mo 8.35 (4.9-8.84 Hz, 1 N), 8.06 (5, g IF; 1 N), 7.94 (d, 9-3.54 Hz, 1 N),

J m SU 7.89 (4, 9-6.57 Hz, 1 H), 7.57 (i,

Um CE 9-8.21 Hz, 1 N), 7.41-7.46 (t,2

NU, 7.11 (d49, 9-8.97, 2.40 Hz, 1 19-M Sm on H), 7.02 (5.1 H), 6.74 (4.9-3.79 | bi (3-trifluoromethylphenyl)-amide 5-(6- (cntet, g Zv Ni 81- cyclopentylaminomethylpyrimidine-4- 191 (t, 2 n). 4 65-14 76 (t 2 yloxy)-indole-1-carboxylic acid n), 150-4 bo (t, 2 n), 1.82-1.44 (t, 2 N).

We are not

There is about; (MeOb) 5 parts/million 8.65 (y, ! U-1.01 Hu, 1 H), 8.37 (a, 9U-8.84

M. M S o HC, 1 H), 8.06 (5, 1 H), 7.95 (4, rya U-3.79 Hz, 1 H), 7.91 (a, 9-2.02 with o nn Hu, 1 H), 7.58 (i, U-7.96 Hz, 1 H), 19-M V, 7.46 (5, 1 H), 7.43 (a, 9-2 ,27 Hz, 525.1 1 H), 7.12 (aa, U-8.97, 2.40 Hu, 1 (3-trifluoromethylphenyl)-amide 5-(6-(2- schi tn vwe gu) rya pyrrolidin-1-ylethylamino)-methyl|- (t, 2 H), ovi What 65 (t, 2 n) and pyrimidine-4-yloxy)-indole-1-carbon 2 BA (t Y n) 4 79 (t 4 n) ' acids " " Sho " I o (meob) 6 parts/million 8.62 (a, t If; 9U-1.01 Hz, 1 H), 8.36 (y, 9-9.09

Hz, 1 N), 8.06 (5, 1 N), 7.95 (y,

M. M C 9-3.79 Hz, 1 N), 7.90 (4, U-8.08

M re Gu, 1 H), 7.65 (5, 1 H), 7.58 (Her, o nn 3-8.08 Hz, 1 H), 7.41 - 7 4b(t,2 19-0 Well, NT (fovi aa hz H), 71 1002729 x- M (ad, 9U-8.97, 2.40 Hz, 1 H), 6.92 - (Z-trifluoromethylphenyl)-amide 5-16- (2-tv from your, ?y) Hz, imidazol-1-ylethylamino)-methyl|-pyrimidine- KI 82 (5, ? no 2 97 (-6 19 hz ? 4-yloxy)-indole-1-carbon acids H ' 7 ' ' '

M o (meob) 6 parts/million 8.64 (a,

E se x U-1.01 Hu, 1 H), 8.34 (a, 9-9.09

Mr. If; Hz, 1 N), 8.05 (5, 1 N), 7.93 (y,

U. SEZ -3.79 Hz, 1 H), 7.89 (a, U-8.08

M Gu, 1 H), 7.56 (i, U-7.96 Hz, 1 H), 19-r -7zho0n 7.39 - 7.45 (t, 2 H), 7.09 (94, 468.0

I I 3-8.84, 2.27 Hz, 1 H), 7.00 (a, (3-trifluoromethylphenyl)-amide 5-(6-U-1.01 Hz, 1 H), 6.73 ( a, 9U-3.54 cyclopropylaminomethylpyrimidine-4-Hz, 1 H), 3.87 (5.2 H), 213-219 yloxy)-indole-1-carboxylic acid t, 1 H), 0.35 - 0 ,48 (t, 4 H). t schi x (meob) 5 parts/million 8.67 (5.1 N),

M ro M 8.37 (a, U-8.84 Hz, 1 H), 8.07 (5,

U. SEZ 1 H), 7.96 (a, 9U-3.79 Hz, 1 H),

M o M 7.50 (a, U-8.34 Hz, 1 H), 7.58 (h, 1 H 3-8.08 Hz, 1 H), 7.43 (h, 9-2.53 198-O MV, Gu, 1 H), 7.46 (5, 1 H), 7.12 (yes, BBZ y-8.97, 2.40 Hz, 1 H), 7.02 (5.1 " o H), 6.76 (a, 9-3.79 Hz, 1 H), 3.95

I I (5.2 H), 3.53 (I, U-6.32 Hz, 2 H), (3-trifluoromethylphenyl)-amide 5-(6-C2-(2- 3.35 (i, 95 .81 Hz, 2 H), 2.89 (5-oxopiperidin-1-yl)-ethylamino|-methyl)- U-6.32 HZ, 2 H), 2.32 (i, 9-6.06 pyrimidine- 4-yloxy)-indole-1-carbonate Hz, 2 H), 1.74 - 1.82 (t, 4 H). acid

Go oseyutnnniaio | njazhsuje (p,

Ge) i where x (СО2Si») b freq./million 8.66 (5.1

M M S H), 8.29 (4, 9-8.84 Hz, 1 H), 7.96

U. CE, (5, 1 H), 7.80 (5, 1 H), 7.66 (a,

M 9-3.54 Hz, 1 H), 7.60 (i, 9-7.96

M on Hz, 2 H), 7.49 - 7.52 (t, 1 H), 19-8 o 7.45 (4, 92.02 Hz, 1 M), 7.18 (aa,|. 526 ,0 u-8.84, 2.27 Hz, 1 H), 7.14 (B. 5., y and 1 H), 6.79 (a, 9U-3.03 Hz, 1 H), ( 3-trifluoromethylphenyl)-amide 5-(6-(2НА, 3.71 (rg. 5., 2 H), 3.60 (bg. 5., 2 65)-2,6-dimethylmorpholin-4-ylmethyl) - H), 2.74 (BG. 8., 2 H), 1.91 (BG. 5., pyrimidine-4-yloxy|-indole-1-carboxylic acid 2 H), 1.15 (y, 9- 6.32 Hz, 6 N). acid (DMSO sv) b parts/million 10.39 (bg.

M (c) 5., 1 H), 8.65 (a, 9-1.01 Hz, 1 H), pe If; 8.29 (y, 9-8.84 Hz, 1 N), 8.13 (a,

Mi 22 M SE 9y-3.54 HZ, 1 H), 8.10 (5.1 H), rya Z 7.98 (a, 9-8.34 Gu, 1 H), 7.65 (i, y-8.08 Hz, 1 N), 7.51 (5.1 N), 19.3 С on she 7.49 (9, 422.53 Hz, 1 N), 715(49.077270 98.97, 2 .40 Hz, 1 H), 7.10 (5.1 (3-trifluoromethylphenyl)-amide 5-(6-((2- H), 6.81 (a, 9-3.79 Hz, 1 H) . y-5.73 Hz, 2 H), 2.60 (i, 4-5.68 Hz, 2 H). o (meob) b freq./million 8.65 (a, ge IF; y 9U-1 ,01 Hz, 1 N), 8.37 (5, 1 N),

And 8.07 (5, 1 H), 7.95 (a, 9-3.79 Hz, and in C 2 H), 7.45 (9, 94-2.02 Hz, 1 H), count 7 .38 (a, 9-19.70 Hz, 1 N), 7.14 1v8-t Su o n (yes, 4-9.09, 2.53 Hz, 1 N), 7.12 5169 (5, 1 N), 6.78 (a, 9-3.79 Hz, 1 N), '

OH 4.37 (9, 9-7.83 Hz, 1 H), 3.78 (4, (-fluoro-3-trifluoromethylphenyl)-amide 643- | 64 gu, 1), 315 (326, hydroxypyrrolidine-1 -ylmethyl)-pyrimidine-4- 1.64 HC, 1 H), 2.84 (4, 921617 yloxy|-indole-1-carboxylic acid HC, 2 H), 2.60 (5, 2 H). th in; (СО2СИи») b freq./million 8.70 (5.1

AND H), 8.29 (4.9-8.84 Hz, 1 H), 7.96

M M Ce (5, 1 H), 7.80 (z, 1 H), 7.66 (a,

E Hm 9-3.79 Hz, 1 NU, 7.60 (5.1 N), 19th Mk o NN 7.49-7.55(t,2H), 7.45(a,9-2 ,53,509.9

Ne Gu, 1 NU, 7.19 (44, 9-9.09, 2.27 (3-trifluoromethylphenyl)-amide 5-16-(2,2,2- y bte oo, be, trifluoroethylamino)-methyl |-pyrimidine-4- 327 Z yy ), 4.00 (5, ), ! and I 27 - 3.34 (t, 2 H). yloxy)-indole-1-carboxylic acid (c)

Su SO u

M. M CE (MeOb) b freq./million 8.66 (5.1 N),

Khm with 8.37 (4, 9-9.09 Hz, 1 N), 8.06 (a, m on Ch-6.06 Hz, 1 N), 7.95 (bg. 5., 2 N) 19-U M ,820 7.44 (5.1 N), 7.37 (9947 Hz, Y | 0 563 not NU, 7.12 (9.9-1.77 Hz, 1 N), 7.14 (4-fluoro-3-trifluoromethylphenyl)-amide 6-11 H), 6.77 (B. 5., 1 H), 3.33 (1,1-dioxo-1-lambda"b"-thiomorpholine-4 (7.5.B H) 3,24 (t, 4 H)ylmethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid

SG osekuyannyun 0 nyamenyumo r gai v; E (meOob) b frequency/million 8.65 (bg. 5.,

Mo M C 1 H), 8.38 (brg. 5., 1 H), 8.07 (ri. r 8., 1 H), 7.95 (bg. 8., 2 H) 7.41 ( in,

I, o n 2 H), 7.14 (bg. 5., 2 H) 6.78 (5, 1 and H), 4.19 (a, U-16.0 Hz, 1 H), 3, 55 19-MU E (9, y-16.0 Hz, 1 N), 3.54 (t, Z H), 007909

OH 3.04 (t, 1 H), 2.76 (t, 1 H), 2.36 (4-fluoro-3-trifluoromethylphenyl)-amide 6- (t 1), 96 (t, 1 NN), 1 77(t,2 ((5)-2-hydroxymethylpyrrolidin-1-ylmethyl)- ), pyrimidine-4-yloxy|-indole-1-carboxylic acid of higher XX R (MeOr) 5 parts/million 8.63 (5, 1 N), c ro M s 8.36 (a, U-8.84 Hz, 1 N), 8.05 (a,

SEh 9-6.32 Hz, 1 H), 7.93 (y, 9-3.79

Khm Hz, 2 N), 7.36 (i, 9-9.47 Hz, 1 N), 19-X M o n 7.43 (a, 92.27 Hz, 1 n), 7.12 (aa 530.9

OH 9-8.84, 2.27 Hz, 1 N), 7.08 (5.1

I I H), 6.75 (a, 9U-3.54 HC, 1 H), 3.59 (4-fluoro-3-trifluoromethylphenyl)-amide I6-(4- (t, C H), 2, 79 (t, 2 H), 2.25 (t, 2 hydroxypiperidin-1-ylmethyl)-pyrimidin-4-H), 1.82 (t, 2 H), 1.54 (t, 2 H). yloxy|-indole-1-carboxylic acid (meob) b parts/million 8.65 (a, fo) E 91.01 Hz, 1 H), 8.35 (a, 9-9.09

TY 7 If; Hz, 1 N), 8.05 (aa, 9U-6.32, 2.78

M. 2 M SE Hz, 1H), 7.93 (y, 9U-3.79 Hz, 1 H),

Chm Z 7.91 - 7.95 (t, 1 H), 7.42 (a, 19-U M-7 o nn 9U-2.27 HZ, 1 H), 7.36 (Y, 9-9 ,73 485.9 n Hz, 1 H), 7.11 (aa, uU-8.97, 2.40 (4-fluoro-3-trifluoromethylphenyl)-amide 5-(6-|HC, 1 H), 7.02 (5.1 H), 6.75 (9, cyclopropylaminomethyl-pyrimidine-4-Y-3.79 Hu, 1 H), 3.88 (5.2 H), yloxy)-indole-1- of carboxylic acid 2.15-2.20 (t, 1 N), 0.35 - 0.49 t, 4 N).

M. o E is Eh If; (acetone-dv) b freq./million 9.60 (5.1

Mo M SE H), 8.63 (5, 1 H), 8.40 (y, U-9.09 ra Z Hz, 1 H), 8.18 (aa, 9U-6.32, 2.78

MK about her Hz, 1 N), 8.05 (a, 9-3.79 Hz, 1 N), 19-27 N E 8.04 -8.11 (t, 1 N), 7.45 - 7 ,51,527.9

E (t, 2 H), 7.18 (ai, 9U-8.97, 2.40 (4-fluoro-3-trifluoromethylphenyl)-amide 5-(6- | Hz, 1 H), 7.12 ( 5, 1 H), 6.79 (y, (2,2,2-trifluoroethylamino)-methyl-Y-3.54 Hz, 1 H), 4.00 -4.03 (t,2 pyrimidine-4- yloxy)-indole-1-carboxylic H), 3.36 - 3.45 (t, 2 H). acid

Me o X E (MeOr) 5 parts per million 8.62 (5, 1 H), i 8.33 (a, U-9.09 Hz, 1 H), 8.03 (aa,

Mo M SE y-6.19, 2.65 Hz, 1 H), 7.91 (bBg. 5., 19-AD r 1 H), 7.90 (a, 9U-3.79 Hz, 1 H ), 446.9

МН, онн 7.39 (а, 9-2.27 Hz, 1 H), 7.33 (І, ' (4-fluoro-3-trifluoromethylphenyl)-amide 6- Z dia A about sv, cad aminomethylpyrimidine- 4-yloxy)-indole-1- and C, s ' y carboxylic acid (a, 423.54 Hz, 1 NU, 3.84 (5, 2 H).

SHIELD and MS (IER)

SG today 01 nyayuoyue Ter, (meob) b frequent./million 8.65 (a,

M (c) E 9-1.01 Hu, 1 H), 8.36 (a, U-8.84 pe IF; Hz, 1 H), 8.05 (49, y-6.32, 2, 78

M. 22 M SE Hz, 1 N), 7.93 (y, 9U-4.04 Hz, 1 N), d-m and ; ooo gts ni tata (t, 1 te, Ts, z, t 7, t, 15-AV S oon she nu), 72 (aa, onvet, oo gts, 00709

H), 7.04 (a, 9-1.01 Hu, 1 H), 6.75 (4-fluoro-3-trifluoromethylphenyl)-amide 6-((2- | (y, U-3.79 Hu , 1 H), 3.87 (5.2 H), hydroxyethylamino)-methyl-I-pyrimidine-4-| -indole-1-carboxylic acid 1 N), 2.74 (5, 1 N), 2.76 (y, 9-5.56 HC, 1 N).

Mao x (DMSO-ov) b frequency/million 8.66 (4, i 9U-1.01 Hz, 1 H), 8.29 (4, 9U-8.84

M. M SE Hz, 1 H), 8.10 (a, 9-3.79 Hz, 1 H), cancer with 7.96 - 7.98 (t, 1 H), 7.67 (, 19- AS MN o nn E 9-6.69 Hu, 1 H), 7.45-7.50 (t,2 | 459.9

H), 7.14 (44, 9-8.97, 2.40 Hz, 1

And you. sphoamide add. | H), 7.04 (5.1 H, ) 6.80 (a, 9-3.79 (2-fluoro-3-trifluoromethylphenyl)-amide 5-(6 methylaminomethylpyrimidin-4-yloxy)-Hz, 1 NU .

Has in; 5., 1 H), 8.65 (a, 9-1.01 Hz, 1 H), and 8.26 (d, 9-9.09 Hz, 1 H), 8.10 (a,

Mo M Ko ee U-3.79 Hz, 1 N), 7.94 (i, 9-7.07 rya Hz, 1 N), 7.70 (i, 9-7.20 Hz, 1 N),

MH o NE 7.A7-7.52 (t, 2 H), 7.14 (499, 19-00 A 4-8.84, 2.53 HZ, 1 H), 7.07 (a, 485, 9 9-1.01 HC, 1 H), 6.82 (9.9-4.29 5-(6- (2-fluoro-3-trifluoromethyl-phenyl)-amide kl Pod yan Co cyclopropylamino-methylpyrimidine-4 - roles, 2 H ' 2 C, in ' 2 yloxy)-indole-1-carboxylic acid that (t,2 H), 023-027 (t,

Mo E (DMSO-dv) b frequency/million 10.35 (bBg. and IF; 5., 1 H), 8.66 (a, 9-1.0 Hz, 1 H),

M. M CE 8.29 (y, U-8.8 Hz, 1 H), 8.07 - r C 8.14 (t, 2 H), 7.97 - 8.05 (t, 1 mi OH H), 7.51 - 7.62 (t, 1 H), 7.49 (4, 19-AE H y-2.3 Hz, 1 H), 7.15 (da, 9U-9.0, 510.0

E 2.4 Hz, 1 N), 7.09 (a, 9-1.0 Hz, 1

H), 6.78 - 6.82 (t, 1 H), 5,85-(4-fluoro-3-trifluoromethylphenyl)-amide 5-(6- | 6.19 (t, 1 H), 3, 81 - 3.88 (t, 2 (2,2-difluoroethylamino)-methyl-pyrimidine- | H), 2.85 - 3.01 (t, 2 H), 2.70 - 4-yloxy)-indole- of 1-carboxylic acid 2.84 (t, 1 N). m. 29 E

There is If; (DMSO-db) b frequency/million 10.39 (5,

M. is M CE 1 N), 8.65 (9, 9-1.0 Hz, 1 N), 8.29

Kh. Z (a, 9-8.8 Hz, 1 N), 8.06 - 8.14 (t,

МН о и 2 Н), 7.96 - 8.05 (t, 1 Н), 7.57 (i,

A 9-9.7 Hz, 1 H), 7.48 (y, U-2.5 Hz, 19-AE and 1 NN), 7.14 (aa, 2-9.0, 2.4 Hz, 1,516.1

I, H), 7.10 (in, 1 H), 6.81 (a, 4-3.3 o Hz, 1 H), 3.58 - 3.83 (t, 6 H), (4- fluoro-3-trifluoromethylphenyl)-amide 5-(6- | 3.43 (aa, 9U-8.7, 4.2 Hz, 1 H), 1.86

CI-"tetrahydrofuran-3-yl)amino|-methyl)- -2.00 (t, 1 H), 1.61 -1.73 (t, 1 pyrimidine-4-yloxy)-indole-1-carbonic H ). acid

SG osekayanyut OC 00nemenyumo r o ES (MmeOb) b frequent./million 8.65 (5.1 N),

Ma X 8.33 (y, 9U-9.09 Hz, 1 H), 8.17 (ad, her If; 96.95, 1.89 Hz, 1 H), 7.92 (y,

M U. 9EZ,79 Hz, 1 H), 7.60 (dav, 98.08, 4.29, 2.27 Hz, 1 H), 7.43 19-DO M" o NE (9, 4- 2.02 Hz, 1 H), 7.44 (i, 459.9

H 99.47 Hu, 1 H), 7.12 (da, 9U-8.84, (2-fluoro-5-trifluoromethylphenyl)-amide 5-(6-|2.27 Hz, 1 H), 7, 00 (5.1 N), 6.77 methylaminomethylpyrimidin-4-yloxy)-(a, 9-3.79 Hz, 1 N), 3.80 (5.2 N), indole-1-carboxylic acid 2, 42 (5, Z H). that and; E (meob) b frequency/million 8.65 (a,

M. M C 91.01 Gu, 1 H), 8.36 (y, 9-9.09 rya Z Hz, 1 H), 7.93 (y, 9-3.54 Hz, 1 H),

MH o nn 7.42 (9, 9-2.02 Hz, 2 N), 7.34 - 19-AN Joon 7.39 (t, 1 N), 7.11 (5, 1 N), 7, 13 520.9 no (ad, 9-2.53 Hz, 2 H), 6.76 (y, (4-fluoro-3-trifluoromethylphenyl)-amide (6- | 979.94 Hz, 1 NU, 3, 99 (5.2 N),

Do-hydroxy-1-hydroxymethyl-ethylamino)- | 293 (9, 925.31 Hu, 2 NU, 3.57 (y, methyl-pyrimidin-4-yloxy)-indole-1- 95.81 Hz, 2 H), 2.77 (t, 1 H). carboxylic acid

M.,0 E (DMSO-dv) b frequent./million 10.39 (bg.

Tj t If; 5., 1 N), 8.67 (a, 9-1.0 Hz, 1 N),

M. 22 M CE 8.29 (a, U-8.8 Hz, 1 H), 8.08 -

Khm Z 8.14 (t, 2 N), 7.95 - 8.04 (t, 1 m o NN NU, 7.57 (I, 9U-9.9 Hz, 1 N), 7.50 (i . ,81 (a, (c) 9UEZ,5 HC, 1 H), 3.62 (5.2 H), 3.44 (4-fluoro-3-trifluoromethylphenyl)-amide 5-I (6- | (9 , 954.3 Hz, 4 H), 2.47 (y, 9-48 (4-acetylpiperazin-1-ylmethyl)-pyrimidin- | Hu, 2 H), 2.40 (y, 954.9 Hz, 2 H), 4-yloxy|-indole-1-carboxylic acid 1.98 (5, 3 H). 68 (in, 1 N), 8.28 (a, U-8.8 and in Cg Hz, 1 N), 8.07 -8.14 (t,2 N), 7.95 - 8.06 ( t, 1 H), 7.76 (5, 1 19-A m On H), 7.57 (Her, 99.9 Hz, 1 H), 7.50 529 1 sho (Z, U-2.3 Hz, 1 N), 7.16 (ad, ; 99.0, 2.4 Hz, 1 N), 7.06 (5.1 N), o 6.80 (y, 9-3.8 Hz, 1 H), 3.66 (5.2 (4-fluoro-3-trifluoromethylphenyl)-amide 5-(6- | H), 3.16 (i, 9-43 Hz, 2 H), 3.05 ( 3-oxopiperazin-1-ylmethyl)-pyrimidin-4-(5, 2 H), 2.64 (Y, 9-5.4 Hz, 2 H).yloxy|-indole-1-carboxylic acid "more; E (DMSO-dv) 6 parts/million 10.36 - (y, wolves ;8, ;-9y1 Hz, ;8, and U. SE - 8.13 (t, 2 N), 7, 97 - 8.04 (t, 1

M H), 7.57 (I, 99.7 Hz, 1 H), 7.50

M o n (ad, 9-2.5 Hz, 1 H), 7.15 (aa, BT? 19-AK o) 99.0, 2.4 Hz, 1 H), 7.04 (a, 9 -08'

OMe Hz, 1 N), 6.80 (y, 9U-3.5 Hz, 1 N), 3.60 (5, Z H), 3.56 (5.2 N), 2.75 - methyl ether 1-(6-P-(4-fluoro-3- 2.83 (t, 2 H), 2.30 - 2.37 (t, 1 trifluoromethylphenylcarbamoyl)-1H-indole-H), 2.09-2 ,18 (t, 2 H), 1.76 - o-yloxy|-pyrimidin-4-ylmethyl)-piperidine- | 1.85 (t, 2 H), 1.51-1.63 (t, 2 4-carboxylic acid H).

ST ostyuaennnnaya 0100 nyameeyume (I, "more; (DMSO-dv) 6 parts/million 10.34 - and de xx 10.45 (t, 1 N), 8.67 (5, 1 N), 8.29

M ro I; C (a, 9-91 Hz, 1 H), 8.13 (a, 9-3.8

X. SEZ Hz, 1 N), 8.10 (5, 1 N), 7.98 (y,

M U-7.8 Hz, 1 H), 7.65 (Her, 9U-8.1 Hz, 1 19-AI. mon H),747-7.53(t,2H),7.09- | 7750

H 7.18 (t, 2 H), 6.81 (a, 9U-3.8 Hz, 1 (3-trifluoromethylphenyl)-amide 5-(6-((2- НУ, 4.54 (i, 9 -48 Hz, 1 H), 4.40 - fluoroethylamino)-methyl|-pyrimidine-4- 4.47 (t, 1 H), 3.83 (5.2 H), 2.76 - yloxy-indole- of 1-carboxylic acid 2.92 (t, 2 N).

M Ge) (DMSO-dv) b freq./million 10.39 (5,

Me If; 1 N), 8.62 (a, 9-1.0 Hz, 1 N), 8.28

M. 2 M s (a, 9-91 Hz, 1 N), 8.13 (a, 9-3.5 r З Hz, 1 N), 8.10 (a, 9-1.3 Hz, 1 H), 7.98 (a, 9-81 Hz, 1 H), 7.65 (i, 19-AM H 9-81 Hz, 1 H), 7.46 - 7.53 (t, 2,498.1

OH H), 7.13 (44, 9-9.0, 2.4 Hz, 1 H), (3-trifluoromethylphenyl)-amide 5-16-K1- 7.08 (a, 9-08 Hz, 1 H), 6.80 (a, hydroxymethylcyclopropyl-amino)-methyl- (9-38 Hz, 1 H), 4.59 (Hi, 955.7 Hz, 1 pyrimidine-4-yloxy)-indol-1- carboxylic H), 3.86 (5, 2 H), 3.34 - 3.40 (t, 2 H acid), 0.39 - 0.50 (t, 4 H). o (DMSO-dv) 6 ppm 10.40 (5, che If; 1 H), 8.66 (y, 9U-1.0 Hz, 1 H), 8.29 (a, 9-9 ,0 Hz, 1 N), 8.13 (a, 9U-3.7

M M C Hz, 1 H), 8.10 (5, 1 H), 7.97 (y, re U-7.8 Hz, 1 H), 7.65 (y, 9U-8.0 Hz,

M o n 1 H), 7.46 - 7.53 (t, 2 H), 7.16 19-AM (c) (aa, 9-9, 0.24 Гцц, 1 НН), 7.04( 5.1 | 568.1

H), 6.80 (a, 9-3.7 Hz, 1 H), 4.05

Ob i (d, 9-7.1 Hz, 2 H), 3.56 (5.2 H), ethyl ether 16-1-(3-trifluoro-002790, UT, o methylphenylcarbamoyl)-1 H-indole- 5-yloxy|- 2 n) 1 7A- i 86 (t o n) 4 48 i pyrimidin-4-ylmethyl)-piperidin-4- 1 63 (t 2 v r 16 ( u-T Hz KI of carboxylic acid H' what ' ' '

E me o EzS g Z (DMSO-yv) b frequent./million 10.99 (bBg.

M. 2 M 5., 1 H), 8.65 (5, 1 H), 8.12 (5, 1 19-AO re H), 7.91 (b. M, 1 H) 7.66( 69-76 4879

ММе, онн HC, 1 H), 7.52(t,2 H), 7.14 (t,2' 5-(b(dimethylamino)methyl)-pyrimidin-4-revoba, H), yloxy) -4-fluoro-2-methyl-M-(3- I I 7 I (trifluoromethyl)-phenyl)-1 H-indole-1-carboxamide

E m. about EzS

Ty t Z (DMSO-yv) b frequent./million 10.99 (bBg.

M. 2 M Z, 1H), 8.64 (in, 1 H), 8.12 (5.1

H), 7.90 (t, 1 H), 7.66 (I, U-7.6 19-AR MNMe o Hz, H), 7.51 (t, 2 8), 715-718 7739 4- fluoro-2-methyl-5-(6-(methylamino)- 5 imported externally 2 methyl)pyrimidin-4-yloxy)-M- b ' b ' and (Z(trifluoromethyl)-phenyl)-1 H-indol- 1- carboxamide

OO Structure/chemical name "H' NMR (400 MHz) Me ШЧА

E me o EzS her Z (mer) 5 8.61 (a, 9U-1.01 Hz, 1

Mo M H), 8.07 (5, 1 H), 7.87 (y, 9-8.84 re Hz, 1 H), 7.55 - 7.62 (t, 1 H),

Y MH o nn 7.A45- 7.51 (t, 2 H), 7.14 (5.1 19-00 H), 7.07 (49, 928.72, 7.45 HZ, 1 500.2

A H), 6.53 (5.1 H), 3.92 (5.2 H),

SH 2.61 (5, C H), 2.19 (t, 1 H), 0.37 5-(6-(cyclopropylamino)-methyl)- -051 (t, 4 H) pyrimidine-4-yloxy) -4-fluoro-2-methyl-M-(3- ! ! (trifluoromethyl)phenyl)-1H-indole-1-carboxamide

IS

"this; kerosene

Y Z x (DMSO-dv) b freq./million 10.99 (5,

M. Zh M 1 H), 8.69 (5.1 H), 8.12 (5.1 H),

M 7.92 (a, U-8.84 Hz, 1 H), 7.86 (Bg.

M 5.1), 7.66 (i, 9-7.96 Hz, 1 N),

MTU on 7.52 (y, 9-8.84 Hz, 1 H), 7.24 (5, 19-AB and 538.8

МН 1), 7.17 (,y-8.21 Hz, 1 N), 6.62 (5.1 N), 3.81 (bg. 5.2 N) (in) 3.23 (Bg 5., 2 H) 3.17 (5.2 H), (3-trifluoromethylphenyl)-amide 4-fluoro-2-|2.77 (Bg. 5., 2 H) 2.59 (in, C N). methyl-5-(6-(3-oxopiperazin-1-ylmethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid

Well, what;

TY Be and (DMSO-4c) b freq./million 10.98 (5,

M. and M 1 H), 8.65 (a, 9U-1.01 Hz, 1 H), p 8.12 (5, 1 H), 7.90 (a, 9-8.7 Hz, 1

M H), 7.66, (I, 9U-8.2 Hz, 1H), 7.53 19-A5 M on (t, 2 H), 7.25 (5, 1 H), 7.15 ( t, 1,570.9

Sm, H), 6.62 (5, 1 H), 3.48-3.55 (g. M,

Ac 8 H) 2.58 (5.3 H), 240 (t, 2 H), (3-trifluoromethylphenyl)-amide 5-(6-(4- 2.00 (5, C H). acetylpiperazine-1 -ylmethyl)-pyrimidin-4-yloxy|I-4-fluoro-2-methylindole-1-carboxylic acid

We WOULD.

Y Z x (DMSO-dv) b freq./million 10.44 (5,

M. and M 1 N), 8.68 (y, 9-1.0 Hz, 1 N), 8.29

Hm (a, 9-91 Hz, 1 H), 8.09 - 8.17 (t, 2 H), 7.98 - 8.06 (t, 1 H), 7.58 (i,

M

19-AT I H 94-99 Hz, 1 H), 7.49 (4, 922.5 Hz, | 526

HnM-y 1 NN), 7.10-7.20 (t, 4 H), 6.81 (a, (4-fluoro-3-trifluoromethylphenyl)-amide 5-(6- | 273.8 Hz, 1 H), 3.94 (5, 2 H), 3.91

CO H-imidazol-2-ylmethyl)-amino|-methyl)- (5.2 H). pyrimidine-4-yloxy)-indole-1-carboxylic acid

ОО остюуаннннинина 0100 nemeoyume STV

E o X (DMSO-ov) b freq./million 10.39 (5, r 1 N), 8.65 (y, 9U-1.0 Hz, 1 N), 8.29

M M SEZ (a, 9-91 Hz, 1 H), 8.13 (a, 9U-3.8

X-m Hz, 1 N), 8.10 (5, 1 N), 7.97 (y,

M o n 9-81 Gu, 1 H), 7.64 (i, 9-81 Hz, (c) 1 H), 7.55 (a, 9-7.8 Hz, 1 H), 7.47 19-ASH -7.52 (t, 2 H), 7.13 - 7.18 (t, 1,581.3

NM H), 7.04 (a, 9-0.8 Hz, 1 H), 6.80 t (a, 9-3.8 Hz, 1 H), 3.71 - 3.88 (t,

I I 1 H), 3.55 (5.2 H), 2.85 (y, (3-trifluoromethylphenyl)-amide 5-(6-(4-9-11.6 Hz, 2 H), 1, 95--2.12 (t, C isopropylcarbamoylpiperidin-1-ylmethyl)-H), 1.48 - 1.70 (t, 4 H), 1.01 (a pyrimidine-4-yloxy|-indol-1- carboxylic y-66 hz. 6 n) ! shk ! acid with fe; (DMSO-av) b part./million 10.30 - ! 10.43 (t, 1 N), 8.67 (5, 1 N) , 8.29

M. 22 M C (a, 9-8.8 Hz, 1 N), 8.13 (a, 9-3.8

Hm and Hz, 1 H), 8.10 (5, 1 H), 7.98 (y, p! o nn y-8.8 Hz, 1 H), 7.65 (Her, 9-81 Hz, 19-AM Hn 0o-520 1 N), 7.47 - 7.54 (t, 2 N), 7.15 534.0

X (aa, 9U-8.8, 2.3 HC, 1 H), 7.08 (5, 1 (3-trifluoromethylphenyl)-amide 5-(6-((2-s. zv) bo zov (t from methanesulfonylethylamino)-methyl-, AI, it' pyrimidine-4-yloxy)-indole-1-carboxylic acid 2.99 (5, C H), 2.95 (M, 9-6.7 Hz, 2 acid H) .

IS

Ma "So E (DMSO-4v) b frequent./million 10.96 (Bg.

Ty 5, 1H) 8.64 (y, 9-1.01 Hz, 1 H),

M. 22 M s, 8.13 (aa, 9U-6.57, 2.53 Hz, 1 H), p Z 7.96 (aa, 9U-4.67, 3.41 Hz, 1 H), 19-AM/ MH about NN 7.59 (I, 99.73 Hz, 1 H), 7.53 (y, 4921 y-8.84 Hz, 1 H), 7.19 (5.1 H), 7.16 (aa, U-8.84, 7.58 Hz, 1 H), a-fluoro-2-methyl-(4-fluoro-3- 6.62 (8, 1 H), 3.75 ( c, 2 H), 2.58 trifluoromethylphenyl)-amide 5-(6- (c, C H), 2.32 (c, C H) methylaminomethylpyrimidin-4-yloxy)- I 7 I I indole-1-carbon acid

IS

E E E p "Soh (MeOb) b freq./million 8.63 (5, 1 H), 8.40 (aa, 9U-7.07, 2.02 HZ, 1 H),

M U. 7.62 (5.2 N), 7.47 (y, 9-10.11 Hz,

M 1 H), 7.11 - 7.13 (t, 1 H), 7.09 19-AH MH O NE (94, 9-1.26 Hz, 1 H), 6.555, 1), |.. 2 3.84 (5, 2 H), 2.65 (5, Z H), 2.44

A-fluoro-2-methyl-(2-fluoro-5-(5, C H).trifluoromethylphenyl)-amide of 5-(6-methylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid

MORE and MS (ER)

ST osyuzhuennnyanyaya 0100 pyaieyayumo TS,

IS

M. o C (DMSO-dv) 6 parts/million 8.67 (5.1 t X Z H), 8.16 (a, U-8.84 Hz, 1 H), 8.07

M. 22 M (5.1 N), 7.97 (a, 9U-3.79 Hz, 1 N), ra 7.950 (a, 9-8.34 Hz, 1 N), 7.58 (i, 19-AU M o) and 97.96 Hu, 1 H), 7.46 (a, 9-7.83 460.0

H Hz, 1 H), 7.14-7.30 (t, 2 H), 4-fluoro-(3-trifluoromethylphenyl)-amide 5-(6- | 9-84 (y, 923.79 Gu, 1 H), 4.03 (5, methylaminomethylpyrimidin-4-yloxy)-2 H), 2.58 (5, C H). of indole-1-carboxylic acid about ES

M X E (DMSO-dv) b parts/million 10.39 (5, her If; 1 H), 8.65 (5, 1 H), 8.28 (a, 9-91

M. 2 M Hz, 1N), 8.08-814 (t, 2 N), p 7.95 - 8.05 (t, 2 N), 7.57 (Y, io, o nn 3-9, 9 Hz, 1 H), 7.49 (y, 9-2.5 Hz, 1 H), 7.15 (aa, 9U-9.0, 2.4 Hz, 1 19-АХ about H),710 (5.1), in, 80 (9.9-35 1002972 μ Hz, 1N), 4.09-4.22 (t, 1 N),

H 3.62-3.77 (t, 2 H), 2.67 -2.77 5-(6-(Z-acetamidopyrrolidine-1- (t, 2 H), 2.39 - 2.48 (t . -1H-indole-1-H), 1.50 - 1.64 (t, 1 H). carboxamide

Example 20 20-A. 5-(b-Methoxymethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide. (6) 0-5 CO

M. 2 In SE, o o nn

To a solution of (3-trifluoromethylphenyl)-amide of 5-(6b-methanesulfonylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (230 mg, 0.46 mmol) was added 1 ml of methanol, then for 5 min. sodium hydride (100 mg, 60 95 in mineral oil) is added in portions. The mixture is stirred at RT for 0.5 h. and then poured into water, extracted with EAs. The extract is dried, filtered and concentrated under reduced pressure. The residue is purified using KFC (Meon with the addition of 1 95

MNAONI/DXM from 0 to 5 95) and get the desired compound.

MS (IER) t/2 443.0 (M--T1); "H NMR (400 MHz, meob) b freq./million 8.63 (5.1 H), 8.36 (y, uU-8.84 Hz, 1

H), 8.06 (5, 1 H), 7.95 (a, 9-3.79 Hz, 1 H), 7.90 (a, 9-8.08 Hz, 1 H), 7.58 (i, 9-7.83 Hu, 1 H), 7.43 (a, 9-2.27

Hz, 2 N), 7.12 (yes, 2-8.97, 2.40 Hz, 1 N), 7.00 (a, 9-1.01 Hz, 1 N), 6.76 (a, 9-3.79 Hz, 1 H), 4.50 (5.2 H), 3.46 (5, Z H).

The following compounds are obtained by a similar method.

MS (ER)

Structure/chemical name IH NMR (400 MHz) t/2

MA

M., 0

That is 7 IF; (meob) 5 parts/million 8.61 (y, 9U-1.01 Hz, 1

M. 22 M SE H), 8.36 (a, U-8.84 Hz, 1 H), 8.06 (5, 1 H), rya 3 17.95 (y, 9-3.54 Hz, 1 H), 7.90 (y, 9-8.34 20-V o o nn Gu, 1 H), 7.57 (, 9U-7.96 Hz, 1 H), 7.42 (y, 471

AH 9-2.27 Hz, 2 N), 7.12 (aa, U-8.97, 2.40'

Hu, 1 H), 7.04 (5, 1 H), 6.75 (y, 9-3.79 Hz, (3-trifluoromethylphenyl)-amide 5-(6- 1 H), 4.55 (5 . carboxylic acid fo) E ty 7 xx (DMSO-dv) 6 ppm 10.40 (5.1 N),

M. and M 8.69 (a, 9U-1.01 Hz, 1 N), 8.29 (a, 9U-8.84 r Sg Hz, 1 N), 8.10 - 8.12 (t, 2H), 7.98 - 8.03

M (t, 1H), 7.55 - 7.58 (t, 1 H), 7.51 (a, 20-C o on 9-2.27 hz, 1 H), 716 (da, 0-8 ,97,2,40 | 790,9

Hu, 1 H), 6.94 (a, 9-1.01 Hz, 1 H), 6.82 (a, (4-fluoro-3-trifluoromethylphenyl)-amide |-3.79 Hz, 1 H) .

Gee)

Ti te x (DMSO-dv) 6 ppm 10.28 (5.1 N),

M. Zh M 8.69 (a, 9-1.01 Hz, 1 H), 8.27 (a, 9U-9.09 r Sgz Hz, 1 H), 8.11 (a, 2-3, 79 Hz, 1 N), 7.94

M (t, 1 H), 7.71 (i, 9-7.20 Hz, 1 H), 7.47 - 20-0 and 7.52 (t, 2 H), 7.16 (da , 9-8.97, 2.40 Hz, 1..790.9

H), 6.93 (y, 9-1.01 Hz, 1 H), 6.82 (a, (2-fluoro-3-trifluoromethylphenyl)-amide |9-3.79 Hz, 1 H), 4 ,48 (5.2 H), 3.39 (5, C 5-(6-methoxymethyl-pyrimidine-4-H).yloxy)-indole-1-carboxylic acid

Example 21: (3-Trifluoromethylphenyl)-amide of 5-16-(acetylaminomethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid. (6) (ee If; U

M. M

Mind SE,

MN oh nn oh

Acetyl chloride (50 mg) and triethylamine were added to a solution of 5-(6-aminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide (50 mg, 0.12 mmol) and THF (5 ml). (50 mg).

The solution is stirred at CT for 10 minutes. and then subjected to partitioning between EIOAc and water.

The organic layer is additionally washed with saline solution. The organic layer is then dried (Mag50"), filtered and concentrated under reduced pressure to obtain the desired compound. MS (ER) t/2 470.0 (MAT); "H NMR (400 MHz, Meob) b frequency/million 8.61 (a, 9U-1.01 Hz, 1 H), 8.34 (a, 2-9.09 Hz, 1 H), 8, 05 (5, 1

H), 7.93 (y, 9-3.54 Hz, 1 H), 7.89 (y, 9-7.83 Hz, 1 H), 7.56 (I, 9-7.96 Hz, 1 N), 7.39 - 7.45 (t, 2 N), 7.09 (yes, 9U-8.97, 2.40 Hz, 1 N), 6.88 (5, 1 N), 6 .73 (a, U-3.79 Hz, 1 H), 4.40 (5, 2 H), 2.01 (5, C H).

Example 22: (3-Trifluoromethylphenyl)-amide of 5-16-(3,3-dimethylureidomethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid. (6)

SSO peacock;

M y o nn (6) M-

Triethylamine was added to a solution of 5-(6-aminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide (50 mg, 0.12 mmol), THF (5 mL), and dimethylcarbamyl chloride (50 mg). (50 mg). In 10 minutes. the solution is partitioned between EIOAc and water. The organic layer is separated and additionally washed with saline solution, dried over Mag5O", filtered and concentrated under reduced pressure to obtain the desired compound.

MS (IER) t/2 499.0 (M--T1); "H NMR (400 MHz, meob) b frequency/million 8.60 (5.1 H), 8.34 (a, 9U-9.09 Hz, 1

H), 8.06 (5, 1 H), 7.86 - 7.95 (t, 2 H), 7.56 (I, U-7.96 Gu, 1 H), 7.38 - 7, 46 (t, 2 H), 7.09 (ai, U-9.09, 2.27

Hu, 1 H), 6.83 (a, 9-1.01 Hu, 1 H), 6.73 (a, U-3.79 Hz, 1 H), 4.36 (5, 2 H), 2.89 (5.6 N).

Example 23: (3-Trifluoromethylphenyl)-amide of 5-16-(methanesulfonylamino-methyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid. (c) in; I am in S

M

MN o nn ot5to

Methanesulfonic anhydride (87 mg, 0.5 mmol) and pyridine (0.2 ml). After 0.5 hours the solution is partitioned between EtOAc and water.

The organic layer is further washed with saline, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by KFC (EOAc/heptane from 10 to 100 Fo) and the desired compound is obtained.

MS (IER) t/2 505.8 (M--1); "H NMR (400 MHz, Meob) b frequency/million 8.64 (y, 9-1.01 Hz, 1 H), 8.36 (a, 9-9.09 Gu, 1 H), 8, 06 (5, 1 H), 7.95 (a, 9U-3.79 Hz, 1 H), 7.90 (a, 9-8.34 Hz, 1 H), 7.58 (Ii, 9U- 8.08 Hz, 1 N), 7.43 (9, 9-2.53 Hz, 1 N), 7.45 (5.1 N), 7.12 (ad, U-8.97, 240 Hz , 1 H), 7.10 (a, 9U-1.01 Hu, 1 H), 6.75 (a, 9-3.79 Hu, 1 H), 4.34 (5, 2 H), 2 .99 (5, Z H).

Example 24: 24-A. 5-(2-chloropyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide.

SI; We are with

M M

Mind SE, about nn

n-butyllithium (1.76 ml, 2, After 10 minutes, a solution of 5-(2-chloropyrimidin-4-yloxy)-1H-indole obtained as described in UMO2006/034833 (0.771 g, 3.32 mmol) in

THF (10 ml). In another 15 minutes. add 3-(trifluoromethyl)-phenylisocyanate (0.88 mL, 6.28 mmol).

Then the solution is allowed to gradually heat up to CT. After 1 hour the solution is concentrated and the residue is transferred to EtOAc and washed with saline. The desired compound is isolated using flash chromatography (10-30 96 E(Ac/heptane).

MS (ER) t/2 433.0 and 434.9 (M-n1). 24-8. 5-(2-Methylpyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide. (6) ov a;

M u. Co

M o nn

To a solution of (3-trifluoromethylphenyl)-amide of 5-(2-chloropyrimidin-4-yloxy)-indole-1-carboxylic acid (example 24-A, 0.150 g, 0.347 mmol), Ra(VizR)»2 (0.009 g, 0.017 mmol) and THF (5 mL) under argon was added MegpsiI (0.35 mL, 2.0 M THF). Then the solution is refluxed for 2 hours. After cooling to RT, THF is removed in vacuo and the residue is purified by flash chromatography (30-75 95 EAs/heptane), then further purified by semi-preparative HPLC to obtain the desired compound.

MS (ER) t/2 413.1 (M-H1);

IN NMR (400 MHz, DMSO-dv) b frequency/million 10.38 (5, 1 N), 8.54 (j, 9-5.6 Hz, 1 N), 8.29 (a, U- 8.8 Hz, 1 N), 8.13 (a, 9-3.8 Gu, 1 N), 8.10 (5.1 N), 7.97 (a, U-7.8 Hz, 1 H), 7.65 (I, 9-8.0 Hu, 1 H), 7.51 (5, 1 H), 7.48 (a, y-2.3 Hu, 1 H), 7.14 (yes, 9-9.0, 2.4 Gu, 1 H), 6.84 (a, 9U-5.8 Hz, 1 H), 6.81 (a, 9U-3.5 Hz, 1 H ), 2.43 (5, Z H).

The following compounds are obtained by a similar method.

MS (ER)

Structure/chemical name IN NMR (400 MHz) t/2

MA

(DMSO-dv) 6 parts/million 10.4 (5.1

H), 8.57 (a, 9U-5.8 Hz, 1 H), 8.29 (y,

M. ,0 3U-9.1 Gu, 1 H), 8.13 (y, 9-3.5 Hz, 1

Y 7 IF; H), 8.10 (5, 1 H), 7.97 (a, U-8.6 Hz,

M. M C 1 H), 7.65 (I, U-8.0 Hz, 1 H), 7.47 - 24-60 X- with |7.54 (t, 1 H), 7.48 ( y, 9-2.5 Hz, 1 455.1 o y H), 7.14 (aa, 2-9.0.2.4 Hz, 1 H), (3-trifluoromethylphenyl)-amide 5-2. ov hz, ve (TM Hz, isobutylpyrimidin-4-yloxy)-indol-1- H), 2.00 -.213 (t, 1 H), 0.84 (4, carboxylic acid -6.8 Hz, 6 H) (DMSO-dv) 6 ppm 10.38 (5.1

H), 8.56 (a, U-5.8 Hz, 1 H), 8.28 (y, 3-8.8 Hz, 1 H), 8.13 (y, 9-3.5 Hz, 1

M 8, H), 8.10 (5, 1 H), 7.98 (a, 9-81 Hz,

IF; 1 H), 7.50 (a, 9-78 Gu, 1 H), 7.48 24-0 AMS (a, 9U-2.3 Hz, 1 H), 7.14 (aa, 9U- 9.0, | 4952 re 3 12.4 Hz, 1 H), 6.82 (y, 9-5.8 Hz, 1 o Hn H), 6.80 (y, 9-3.5 Hz, 1 H), 2.57 (y, (3-trifluoromethylphenyl)-amide 5-(2-po x (Shsch vnu, and cyclohexylmethylpyrimidin-4-yloxy)-indol-4 19; 2 N o yav o ov NN 1-carbonov acid "19 (t, 2 N), 0.86 - 0.98 (t, 2 N).

M o (SOSI") b frequency/million 8.69 (y, U-0.8 pe If; Hz, 1 N), 8.23 (4.3-8.8 Hz, 1 N),

M. Zh M S 7.86 (5, 1 NU, 7.78 (a, U-81 Hz, 1 r Z H), 7.60 (a, 9-3.8 Hz, 1 H), 7, 50 - 24-E M 7.58 (t, 2 H), 7.44 -7.49 (t, 1 H),|Y. 413.1 o n 7.41 (a, 9-2.3 Hz , 1 H), 7.16 (aa, (3-trifluoromethylphenyl)-amide 5-(6-y-8,9, 2.3 HZ, 1 H), 6.76 (5.1 H), methylpyrimidine 4-yloxy)-indole-1-carboxylic acid | 6.72 (a, 9-34 Hz, 1 H), 2.52 (5, C acid H).

M. 0 (DMSO-dv) 6 ppm 10.38 (5, 1 pe If; H), 8.64 (a, 4-1.0 Hz, 1 H), 8.28 (4,

M. 2 M C 3-9.0 Hz, 1 H), 8.13 (y, 9-3.7 Hz, 1

Khm Z H), 8.10 (5, 1 H), 7.97 (a, U-8.6 Hu, 1 H), 7.65 (I, U-8.0 Hz, 1 H), 7 ,47 - ha OH 7.53 (t, 2 H), 7.14 (49, 4-9,0,2,4. |. 799

Hu, 1 H), 6.94 (a, U-0.9 Hz, 1 H), (3-trifluoromethylphenyl)-amide 5-(6- 6.680 (a, 9U-3.4 Hz, 1 H), 2.57 (y, isobutylpyrimidin-4-yloxy)-indol-1-ue71 Hz, 2 H), 2.00 - 2.18 (t, 1 carboxylic acid H), 0.90 (a, 9U-6, 7 Gu, 6 H)

Example 25: (3-Trifluoromethylphenyl)-amide of 5-(2-hydroxymethylpyridin-4-yloxy)-indole-1-carboxylic acid 25-A. Tert-butyl ether of 4-chloropyridine-2-carboxylic acid. ; and SI 2 o 4-Chloropyridine-2-carbonyl chloride d"hydrochloride (publication Oga. Rgos. Vev. YuOeum. 2002, 6, 777) (17.0 g, 81.3 mmol) are transferred to THF (200 ml) and added in portions sodium tert-butoxide (23.4 g, 243.5 mmol). After 1.5 h, the mixture was diluted with water (500 mL) and extracted with EOAc (2 x 500 mL). The combined organic layers were dried (Mg5O4), filtered and then concentrated. The residue was then purified by KFC (10-30 96 EOAc/heptane) to give the desired compound. MS (ER) m/2 213.9 and 215.9 (Mat) 25-8. Tert-butyl ether 4 -(1H-indol-5-yloxy)-pyridine-2-carboxylic acid.

And I

M M

N o) AH.

B-Hydroxyindole (100 mg, 0.72 mmol), 4-chloropyridine-2-carboxylic acid tert-butyl ether (160 mg, 0.72 mmol) and cesium carbonate (245 mg, 0.72 mmol) were combined in DMSO (1.5 ml) and heated at 105 °C for 3 h in a sealed tube. The reaction mixture was cooled to RT and partitioned between EtOAc and brine. The organic layer was separated, dried over anhydrous Mag5O4, filtered and concentrated. The residue was purified with the help of KFH (from

EtOAc/heptanes 2:8 to EtOAc) and obtain the desired compound. MS (ER) t/2 311.1 (M--1); "H NMR (400

MHz, DMSO-av) b frequency/million 11.29 (Brg. 5., 1 H), 8.50 (a, 9-5.8 Hz, 1 H), 7.50 (a, 9-86 Hz, 1 H), 7.46 (y, y-2.8 Hz, 1 H), 7.37 (t, 2 H), 7.07 (aa, Y-5.6, 2.5 Hz, 1 H), 6.91 (aa, 9-8.6, 2.3 Hz, 1 H), 6.47 (I, 9-21 Hz, 1

N), 1.51 (5.9 N). 25-S. 4-(1-(3-Trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyridine-2-carboxylic acid tert-butyl ether

C in; s) in the HU SEZ

M o AH. (c) N

A solution of n-butyllithium (0.75 ml, 1.20 mmol, 1.6 M in hexanes) is added to a pre-cooled (-78 "С) solution of 2,2,6,6-tetramethylpiperidine (0.22 ml, 1.30 mmol) and THF (5 mL). After 15 min, a solution of 4-(1H-indol-5-yloxy)-pyridine-2-carboxylic acid tert-butyl ether (310 mg, 1.00 mmol) in THF (2 After another 0.5 h, 3-trifluoromethylphenylisocyanate (0.27 mL, 2.00 mmol) was added. The reaction mixture was then allowed to warm to RT and stirred for 3 h. The reaction mixture was then partitioned between EAs and a buffer solution with pH 7. The organic substances are separated and dried over anhydrous Mag50". After concentration, the residue is purified using

KFC (from EIHUOAc/heptanes 1:9 to E(OAc/heptanes 7:3) and obtain the desired compound. MS (ER) t/2 498.2 (MAT); "H NMR (400 MHz, CO"2Sig) b freq./million 8.41 - 8.47 (t, 1 N), 8.37 (v, 1 N), 8.34 (y, 9-91 Hz, 1 N), 7.97 (v, 1 H), 7.85 (a, U-8.3 Hz, 1 H), 7.73 (a, 9-3.5 Hz, 1 H), 7.63 (j, 1 H), 7.57 (i, 9-81 Hu, 1 H), 7.46 - 7.51 (t, 1 H), 7.38 (0, 1 H), 7.13 (ai, 9U-9.0, 2, 4 Hz, 1 H), 6.92 (da, U-5.6, 2.5 Hz, 1 H), 6.69 (a, 9U-3.8 Gu, 1

N), 1.60 (5.9 N). 25-0. (3-Trifluoromethylphenyl)-amide of 5-(2-hydroxymethylpyridin-4-yloxy)-indole-1-carboxylic acid

C in;

U. Xia

M on o n

Tert-butyl ether of 4-(1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyridine-2-carboxylic acid (400 mg, 0.80 mmol) is dissolved in THF (10 ml) at 0 "С and then lithium aluminum hydride (2.4 mL, 2.40 mmol, 1.0 M solution in ether) was added.The reaction mixture was allowed to warm to room temperature over 3 h, then quenched and partitioned between EtOAc and saturated aqueous MNaCl. The organics were dried over anhydrous Mag5O4 and purified by KFC (from EtOAc/heptanes 3:7 to EOAc) to give the desired compound as a white solid (182 mg, 53 95). MS (ER) t/2 428.1 ( Mat); "H NMR (400 MHz, DMSO-av) b freq./million 10.39 (5, 1 H), 8.29 - 8.37 (t, 2 H), 8.15 (y, 9U -3.8 Hz, 1 H), 8.09 (5, 1 H), 7.98 (a, U-8.5 Hz, 1 H), 7.65 (I, 9-8.0 Hz, 1 H), 7.50 (a, 9-7.7 Hz, 1 H), 7.47 (a, 9-24 Gu, 1 H), 7.13 (da, U-8.9, 2, 5 Hz, 1 H), 6.92 (a, y-2.4 Hz, 1 H), 6.77 - 6.85 (t, 2 H), 5.35 (I, Y-5.8 Hz , 1 N), 4.49 (a, 2-5.8 Hz, 2 N).

Example 26 26-А. 4-1-(3-Trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|pyridin-2-ylmethyl ether of methanesulfonic acid.

C in; o x S

hmm

ОМ5 about nn

Methanesulfonyl chloride (0.2 ml, 2.46 mmol) was added at room temperature to a solution of (3-trifluoromethylphenyl)-amide of 5-(2-hydroxymethylpyridin-4-yloxy)-indole-1-carboxylic acid, the compound of example 25-O (700 mg, 1.64 mmol) and triethylamine (0.7 mL, 4.92 mmol) in DCM (50 mL). After 1 hour the reaction mixture is partitioned between DCM and a saturated aqueous solution of Mansoz. The organic layer is separated, dried over anhydrous magnesium sulfate, concentrated, and then purified by KFC (from

EtOAc/heptanes 2:4 to EtOAc/heptanes 9:1) and obtain the desired compound. MS (IER) t/2 506.0 (M-n1). 26-8. (3-Trifluoromethylphenyl)-amide of 5-(2-(isopropylaminomethyl)-pyridin-4-yloxy|-indole-1-carboxylic acid

C in;

Mo M school

AH-m xx (in) N

A solution of methanesulfonic acid 4-(1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|pyridin-2-ylmethyl ether) (150 mg, 0.30 mmol) and isopropylamine (5 mL) was stirred at RT for 2 h. The reaction mixture is concentrated under reduced pressure and the residue is purified using semi-preparative HPLC (C18; 10-100 95 ACN/HgO with the addition of 0.195 MNAOH) to obtain (3-trifluoromethylphenyl)-amide 5-(2-(isopropylaminomethyl)-pyridine-4- yloxy|-indole-1-carboxylic acid.

MS (IER) t/h 469.2 (M--1); "H NMR (400 MHz, Meob) b frequency/million 8.25 - 8.37 (t, 2 H), 7.97 (5, 1 H), 7.88 (a, 9-3.8 Hz , 1 H), 7.80 (a, 9-81 Hz, 1 H), 7.48 (her, U-8.0 Gu, 1 H), 7.36 (a, U-7.6 Hz, 1 H), 7.30 (a, 9-2.3 Gu, 1 H), 7.00 (aa, 9U-9.0, 2.4 Hz, 1 H), 6.90 (a, 9- 2.3 Hz, 1 H), 6.81 (aa, 9-5.8, 2.3 Hz, 1 H), 6.66 (y, 2-3.8 Hz, 1

N), 4.01 (5.2 N), 3.09 - 3.18 (t, 1 N), 1.18 (a, 9-6.6 Hz, 6 N).

The following compounds are obtained by a similar method. with. MS (ER)

SG bizhyuyanyunninoya 000 10nyameyuyuo Ge, (mer) b chast./mln 8.23 - p p; 8.33 (t, 2 H), 7.97 (v, 1 H), 7.87 (a, 9-3.8 Hz, 1 H), 7.80 (a,

M. M S oyu 3-8.3 Hz, 1 H), 7.48 (her, 9-81 re Hz, 1 H), 7.35 (a, 9-78 Hz, 1

МН о нн Н), 7.30 (а, 9-23 Hz, 1 Н), 26-2 K 7.00 (94а, 4-9, 0.24 Hz, НН), 07972 6.90 (а, 9-23 Hz, 1 H), 6.78 (3-trifluoromethylphenyl)-amide 5-(2-oz et 23 ni z 95 cyclopropylaminomethylpyridin-4-yloxy)-B) 2 28 Sh ov (t and B) 0 44 Indole-1-carboxylic acid acid 0 59 /t A N y shk (mer) b chast./million 8.24 - sh- y; 8.33 (t, 2 H), 7.97 (v, 1 H), ! 7.87 (a, 9-3.8 Hz, 1 N), 7.81 (a,

M. 2 M C 3-81 Hz, 1 N), 7.48 (I, 9U-8.0 rya with Hz, 1 N), 7.35 (a, 9-78 Hz, 1 26-00 МН o nn H), 7.30 (9, 9-23 Hz, 1 H), 441.2 7.60 (aa, 9-9, 0.24 Hz, 1 H), (3-trifluoromethylphenyl)-amide 5- (2- 6.89 (a, va and Ai methylaminomethylpyridin-4-yloxy)-indol-1-nahy p Nu Z tav. 2 carboxylic acid NI, 2.33 (v, З H).

SHI and MS (IER)

SG osyakovanninny 00 0nyaeeyume Ir o (mer) b freq./million 8.28 (a, sxhe x 98.8 HZ, 1 H), 8.21 (a, 9-5.8

M ro IF; SU Hz, 1 N), 7.97 (5, 1 N), 7.87 (a,

SE, 93.8 HZ, 1 H), 7.81 (a, y9-8.1

X-m Hz, 1 N), 7.48 (Her, 9-81 Gu, 1 26-E m o nn NU, 7.35 (y, 9-7.3 Hz, 1 N), 497.3

Mo 7.29 (y, 9-23 Hz, 1 N), 6.95 - 7 t,2 H 7 - (3-trifluoromethylphenyl)-amide 5-(2-morpholine-4-5 1 n) and imported ylmethylpyridin-4-yloxy)-indole-1-carboxylic acid 1n), 352 -73.58 (t, A n), 347 acid 5, 2N), 2.31 - 2.41 (t, 4N). (mer) b freq./million 8.22 - 8.32 (t, 2 H), 7.97 (v, 1 H), (o) 7.87 (a, 9-3.5 Hz, 1 H ), 7.80 (a, with If; h-8.1 HC, 1 H), 7.48 (i, 2-80

M. J M C Hz, 1 H), 7.35 (a, 9U-8.6 Hz, 1

Kh-m "| tbo (aa, chayu, 24 Hz V)

H (aa, 9U-5.8, 2.5 Hz, 1 H), 6.66 (3-trifluoromethylphenyl)-amide 5-(2- (a, 9-3.5 Hz, 1 H), 3, 78 - 3.88

IKtetrahydropyran-4-ylamino)-methyl|-pyridine-4- | (t, 4 H), 3.24 - 3.32 (t, 2 H), yloxy)-indole-1-carboxylic acid 2.59 - 2.74 (t, 1 H), 1.68 - 1, 82 (t, 2 H), 1.26 - 1.41 (t, 2 H). (mer) b freq./million 8.21 - s (6) 8.33 (t, 2 H), 7.97 (v, 1 H),

If; 7.87 (a, 9-38 Hz, 1 N), 7.81 (a,

MA. 22 M SE U-8.1 Hz, 1 N), 7.49 (I, 9-81 rya Z Hz, 1 N), 7.35 (a, 9U-7.8 Hz, 1

H), 7.30 (y, 20-2.3 Hz, 1 H), 26-8 C on OH 7.00 (aa, U-90, 24 Hz), 1071 6.92 (y, 9-2 .5 Hz, 1 H), 6.74 (Z-trifluoromethylphenyl)-amide 5-(2-((2- (aa, 9-5.8, 2.5 Hz, 1 H), 6.66 hydroxyethylamino) -methyl|-pyridin-4-yloxy)- | (y, 93.8 Gu, 1 H), 3.75 (5.2 indole-1-carboxylic acid NU, 3.55 (y, y-5.6 Hu, 2 N), 2.63 (i, 9-5.6 Hz, 2 N). sh- i; E (MeOb) b freq./million 8.16 - ! 8.32 (t, 2 N) , 7.95 (yes, U-6.3,

Mo M C 2.8 Hz, 1 H), 7.77 - 7.87 (t, 2 rya Z H), 7.18 - 7.32 (t, 2 H), 6.99 26-H МН o nn (ai, U-8.8, 2.3 Hz, 1 H), 6.89 459.1 (a, 9U-2.3 Hz, 1 H), 6.73 (ai, (4-fluoro- 3-trifluoromethylphenyl)-amide 5-(2-to,B, 2.3 Hz, 1 H), 6.65 (j, methylaminomethylpyridin-4-yloxy)-indol-1- 525.5 p 3.67 (5 ,2 N), carboxylic acid " " I

Example 27 27-А. (4-Fluoro-3-trifluoromethylphenyl)-amide b-tetrazol-2-ylmethylpyrimidin-4-yloxy)-indole-1-carboxylic acid. c) "She IF; E what mom on

M

Man (27 mg, 0.68 mmol) was added to a solution of 1H-tetrazole (48 mg, 0.68 mmol) in DMF (3 ml) at 0 °C. After 30 min, 6-(1-(4-fluoro) was added -3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-

methanesulfonic acid pyrimidine-4-ylmethyl ether (300 mg, 0.57 mmol) and the reaction mixture was allowed to warm to RT and then stirred overnight. Add a saturated solution of ammonium chloride (2 ml), then EAs (4 ml). The layers are separated and the aqueous layer is further extracted with EtOAc (3x). The combined organics are evaporated and dried to give the crude product. The residue is purified by HPLC on silica gel (elution in gradient mode: from 100 90 DHM to 98 956 DHM - 2 906 MeonN) and the desired compound is obtained. MS (ER) t/2 499.1 (M.H1);

NMR NMR (400 MHz, Meor) 5 ppm 8.78 (5, 1 N), 8.63 (y, U-1.01 Hz, 1 N), 8.35 (a, 9U- 9.09 Hz, 1 H), 8.05 (aa, 9-6.06, 2.53 Hz, 1 H), 7.93 (a, 9-3.79 Hu, 2 H), 7.42 (a, 9-2.27 Hu, 1 H), 7.36 (I, 2-9.60 Hz, 1 H), 7.11 (da, 9-9.09, 2.53 Hu, 1 H ), 6.88 (5, 1 N), 6.75 (a, 9-3.79 Hz, 1 N), 6.03 (5, 2 N).

The following compounds are obtained by a similar method.

MS (ER)

Structure/chemical name Н"N NMR (400 MGu) t/2

MA

(in)

SO KY

(MeOb) 5 ppm 9.33 (5.1 N), 8.62

MMS (a, 9-1.01 Hz, 1 H), 8.34 (a, 9-8.84 Hu, 1 ra rya H), 8.04 (ad, U-6.32, 2, 78 Hz, 1 N), 7.92 27-58 M M o nn (a, 9U-3.79 Hz, 2 N), 7.41 (a, 90-227 Hz, 1 | 4991

Mem H), 7.35 (I, 9-9.60 Hz, 1 H), 7.10 (aa, . . 98.97, 2.40 Hz, 1 H), 6.97 (5, 1 H ), 6.74 (4-fluoro-3-trifluoromethylphenyl)-amide (a, 9-3.79 HC, 1 H), 5.82 (c, 2 H) b-tetrazol-1-ylmethylpyrimidin-4-' 1 yloxy)-indole-1-carboxylic acid (c)

SO (xx

M M SE. | (MeOb) b frequency/million 8.53 (0.9U-1.01 Hz,

Arya 1 H), 8.22 (a, 9-9.09 Hz, 1 H), 7.94 (aa,

M'M o nn 96.19, 2.65 Hz, 1 H), 7.79 - 7.84 (t, 2 27-6 - H), 7.22 - 7.28 (t, 2 H), 6.96 (aa, 525.9 3-8.84, 2.27 Hz, 1 H), 6.61 (t, 2 H), 6.34 (4-fluoro-3-trifluoromethylphenyl)-amide im C Nu 5.04 (5.2 H), 217 (in, 3 H), 1.91 acid (6) ha X E

M. Zh M SE (DMSO-av) 6 parts/million 10.39 (5.1 N), r with I8.58-8.77 (t, 2 N), 8.23 - 8.32 (t . 9.7 Hz, 1 N), 7.49 (a, 9-2.3 Hz, | 498.0

M 1 H), 7.14 (da, 9U-9.0, 2.4 Hz, 1 H), 6.87 (4-fluoro-3-trifluoromethylphenyl)-amide |(a, 9-1.0 Hz . ylmethylpyrimidin-4-yloxy)-indole-1-carboxylic acid about ES

Mu IF; (meOb) 5 parts/million 8.64 (y, 9U-1.01 Hz, y 1 H), 8.30 (a, 9U-8.84 Hz, 1 H), 8.17 (aa,

M. 2 M 9-7.07, 2.02 Hz, 1 H), 7.91 (y, 9U-3.54 Gu, p 1 H), 7.60 (a, 9-2.53 Hz, 1 H), 7.56 (a, 27-E M' o nn E 91.77 Hu, 1 H), 7.56 - 7.62 (t, 1 H), 496.9 z, 7.44 ( 1, 9-9.35 Hz, 1 N), 7.37 (a, 9-2.27 , , Hz, 1 N), 7.07 (aa, 9U-8.97, 2.40 Hz, 1 H), (2-fluoro-5-trifluoromethylphenyl)-amide 6.75 (a, 93.79 Hz, 1 H), 6.37 (i, 92.15) 5-(6-pyrazol-1-ylmethyl-pyrimidine -4- HC, 1 H), 6.39 (5, 1 H), 5.45 (in, 2 H). /mln 8.66 (5.1 H), 8.31

M. Zh M (a, 9U-9.09 Hz, 1 H), 8.17 (da, 9U-6.95,

Khm vosti Na, 7, 5, 7, t, her, ; 27-E MU On R 9-2.53 Hz, 1 N), 7.45 (1.9U-9.35 Hz, 1 N), | 496.9 - in 720--7.21 (t, 1 H), 7.09 (44.4-9.09, (2-fluoro-5-trifluoromethylphenyl)-amide 2.21 HC, 1 H), 7.02 (5.1 H), 6.75 (y, 5-(6-imidazol-1-ylmethyl-pyrimidin-4- | 9-3.79 Hu, 1 H), 6.63 (5, 1 H), 5.33 (5.2 yloxy)-indole-1-carboxylic acid | H).

Co, Pe g 7 If; (DMSO-dv) b frequency/million 10.39 (bg. 5., 1

M. 2 M H), 8.70 (a, 9-1.0 Hz, 1 H), 8.27 (a, U-8.8 rya Hz, 1 H), 8.08 - 8.14 ( t, 2 N), 7.95 - 8.04

M, o nn (t, 1 H), 7.57 (Her, 9U-9.7 Hz, 1 H), 7.47 (y, 27-44 thing 9-2.5 Hz, 1 H), 7 ,12 (yes, 9-9,0,24Hz,1| 512,0

NM NO, 6.79 (a, 9U-3.5 Hz, 1 N), 6.66 (a, 9-1.3 ? I I Hz, 1 N), 6.50 (a, 9U-0, 8 Hz, 1 H), 6.44 (a, (4-fluoro-3-trifluoromethylphenyl)-amide 91.5 Hu, 1 H), 5.37 - 5.46 (t, 2 H), 5.05 5-(6-(2-amino-imidazol-1-ylmethyl)- (5, 2 H). pyrimidine-4-yloxy|-indole-1-carboxylic acid (6) he IF; E (acetone-dv) b freq./million 10.66 (5.1 N),

MM C 9.19 (5, 1 N), 8.98 (a, 9U-9.09 Hz, 1 N),

Drya 8.60 (ad, 9U-6.32, 2.53 Hz, 1 N), 8.76 (y, 27-N M M o nn 3-3.79 Hz, 1 N), 8.68 (aa, 9U-8.84, 3.79 5iIZ9

Mem Hz, 1 H), 8.03 (a, 9-2.27 Hz, 1 H), 7.99 (i, " . . 3-9.73 Hz, 1 H), 7.73 (yes, 9U-8.97, 2.40 (with fluorine Z trifluoromethylphenyluamia lu Nut va 73037 above: . Hz, 1 H), 6.37 (5, 2 H), 3.20 (5, C H). pyrimidine-4 -yloxy|-indole-1-carboxylic acid (c)

SSO uh

M. Ж M SE (acetone-dv) b freq./million 10.67 (5, 1 N), r z 19.24 (5, 1 N), 9.01 (a, 9U-9.09 Hz, 1 H), m. o and 8.83 (ai, U-6.32, 2.53 Hz, 1 H), 8.78 (a, 274 Ko M 3-3.79 Hz, 1 H), 8 .72 (yes, 9U-8.08, 3.79 5iIZ9

Me Hz, 1 H), 8.01 - 8.07 (t, 1 H), 8.06 (a, 9-2.02 Hz, 1 H), 7.76 (da, 9U-8.97, 2.40 (4-fluoro-3-trifluoromethylphenyl)-amide | Hz, 1 H), 7.51 (in, 1 H), 7.34 (j, 9-3.54 6-(5-methyltetrazole-2 -ylmethyl)- Hz, 1 H), 6.57 (5.2 H), 3.09 (5, C H). pyrimidine-4-yloxy|-indole-1-carboxylic acid

E.S

GF) With es U. (DMSO-dv) 6 parts/million 10.38 (bg. 5., 1

M. M H), 8.70 (9, 9-1.0 Hz, 1 H), 8.29 (a, U-9.1 27-4 M M o nH Hz, 1 H), 8.06 - 8.17 (t, 2 H), 7.96 - 8.05 540

Lem (t, 1 H), 7.57 (Y, U-9.9 Hz, 1 H), 7.50 (y, "

NM 9U-2.5 HZ, 1 H), 7.15 (44, 9-9.0, 2.4 Hz, 1 (4-fluoro-3-trifluoromethylphenyl)-amide | H), 6.77 - 6 .88 (t, 4 N), 5.50 (5.2 N). 5-I(I6-(5-amino-tetrazol-1-ylmethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid

CO school

M M SE, (DMSO-dv) 6 ppm 10.40 (5.1 N),

AM. X-m 8.70 (a, 9-1.0 Hz, 1 N), 8.28 (a, 9-91 Hz,

M "M o nn 1 NN), 8.11 (a, 2-38 Hz, 2 H), 7.95 - 8.06 27-K Me (t, 1 H), 7.57 (1, 9U- 9.9 Hz, 1 N), 7.51(a4, | 514.0

МН у-2.3 Hz, 1 H), 7.16 (ай, 9У-9.0, 24 Гу, 1 ? I I H), 7.00 (5, 1 H), 6.81 (a, 9-3.3 Hz, 1 H), (4-fluoro-3-trifluoromethylphenyl)-amide 6.08 (y, 9U-5.3 Hz, 1 H), 5.76 (5, 2 H). 5-(6-(5-amino-tetrazol-2-ylmethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid

There is phi; ! (DMSO-dv) 6 parts per million 8.69 (y, 1 H), and in S oyu 8.28 (a, 9-8.8 HC, 1 H), 8.13 (a, 9-3 ,8 Hz,

Mrya 1 H), 8.08 - 8.11 (t, 1 H), 7.95 - 8.00 (t, 27th M' o nn 1 H), 7.88 (5, 2 H) . ,4 (3-trifluoromethylphenyl)-amide 5-(6- Hz, 1 p.) and what is new in KA (9,

1,2,3)triazol-2-ylmethyl-pyrimidin-4-TC, b' and yloxy)-indole-1-carboxylic acid

There is phi; (DMSO-4bv) b frequency/million 10.39 (5.1 N), ! 8.70 (a, 9-1.0 Hz, 1 N), 8.28 (a, 9-91 Hz,

MM S by 1 H), 8.25 (a, 9U-0.8 Hz, 1 H), 8.13 (a, rya 3-3.8 Hz, 1 H), 8.08 - 8.11 (t, 1 N), 7.95 27-M MU, o nn - 8.01 (t, 1 N), 7.60 (a, 9U-1.0 Hz, 1 N), 480.0

MEM 7.65 (I, Y-8.0 Hz, 1 H), 7.47 - 7.53 (t, 2 (3-trifluoromethylphenyl)-amide 5-(6- couvu) vu a and v VI

I1,2,3)triazol-1-ylmethyl-pyrimidin-4-5 77 (in 2 n) shk ' ' ' ' yloxy)-indole-1-carboxylic acid " " I (6)

OO 2

M M SE, | (Meob) b frequency/million 8.62 (y, 9U-1.01 Hz,

H Hm 1 H), 8.32 (a, 9U-9.09 Hz, 1 H), 8.05 (aa,

M o nn u-6.19, 2.65 Hz, 1 N), 7.90 - 7.95 (t, 2 se N), 7.34 - 7.39 (t, 2 N), 7.22 (y, 9-2.53 gm s Hz, 1 N), 7.05 (da, U-8.97, 2.40 Hz, 1 N), |. 2799

M. 6.94 (5, 1 N), 6.73 (a, 9-3.79 Hz, 1 N), . . 5.46 (a, 9-2.27 Hz, 1 H), 4.37 (5.2 H), (4-fluoro-3-trifluoromethylphenyl)-amide 3.63 (5, 3 H). 6-(1-methyl-1H-pyrazole-3-ylamino)-methyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid

Example 28 28-А. 4-1-(3-"Rifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyridine-2-carboxylic acid

With So

Mo M p

H-k o on o nn

A solution of 4-P1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyridine-2-carboxylic acid tert-butyl ether (1 g, 2.01 mmol) and TFA (20 mL) was stirred at RT for 2 hours The reaction mixture is concentrated in vacuo and used in the next stage without additional purification. MS (IER) t/ 442.0 (M.n1). 28-8. 5-(2-Methylcarbamoylpyridin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide.

C in;

M u. ear

M o tn o nn

A mixture of 4-(1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyridine-2-carboxylic acid (150 mg, 0.27 mmol), DCM (3 mL) and triethylamine (0.11 mL , 0.81 mmol) are stirred at 0 "C and oxalyl chloride (0.27 ml, 0.54 mmol, 2.0 M solution in DCM) is added. After 30 minutes, excess methylamine (2.0 M solution in DCM) is added. After another 30 min, the reaction mixture was partitioned between DCM and a saturated aqueous solution of ManHsCO 3 .The organic layer was separated and dried over anhydrous

Mag5O". After concentration, the residue is purified by means of semi-preparative HPLC (C18; 10-100 96 ACN/H2HO with the addition of 0.1 95 MNAOH) and the desired compound is obtained. MS (ER) t/2 455.2 (M-H1);

NMR NMR (400 MHz, Meob) b frequency/million 8.36 (y, 9-56 Hz, 1 H), 8.29 (a, U-8.8 Hz, 1 H), 7.97 (5, 1 N), 7.87 (a, 9-3.8 Hz, 1 N), 7.81 (a, 2-8.3 Hz, 1 N), 7.47 - 7.52 (t , 1 H), 7.45 (y, 9U-2.5 Hz, 1 H), 7.35 (а, 9-7.8 Hz, 1

H), 7.91 (a, 9-23 Hz, 1 H), 7.01 (ad, 92-9.0, 2.4 Hz, 1 H), 6.96 (aa, U-5.6 , 2.5 Hz, 1 N), 6.66 (a, U-3.8 Hz, 1

H), 2.83 (5, C H).

The following compounds are obtained by a similar method.

ST seyuunnnninya 100 yameayum Ter (6) vva; in M still (meob) 5 parts/million 8.42 (y, 9-56 r with Hz, 1 H), 8.31 (a, 9-91 Hz, 1 H),

M o y 7.97 (5, 1 H), 7.67 (a, 9U-3.8 Hz, 1 o); H), 7.81 (a, 9-8.3 Hz, 1 H), 7.56 (y, 28-60 M 9-2.3 Hz, 1 H), 7.48 (I, 9-81 Hz, 1,521.1

X M H), 7.40 (a, 9-2.3 Hz, 1 H), 7.30 - 7 7.38 (t, 2 H), 6.98 - 7.06 (t, 2 H) . 92.5 Hz, 1 H), 3.73 (5, C H). pyridin-4-yloxy|-indole-1-carboxylic acid. (c) in o M more (meob) 5 ppm 8, 36 (y, U-5,6

X- with Hz, 1 N), 8.29 (a, 9-91 Hz, 1 N),

M o them 7.97 (5, 1 H), 7.86 (a, U-3.8 Hz, 1 o H), 7.81 (a, 9-81 Hz, 1 H), 7.43 - 28-00 I 7.52(t,2 N), 7.27 -7.38(t,2 N), 538.2

M 6.93 - 7.04 (t, 2 N), 6.66 (a, U-3.5 7 Gu, 1 N), 3.46 (, U-6.7 Hz, 2 N), 2 ,64 (I, U-6.7 Hz, 2 H), 2.54 (Bg.5., (3-trifluoromethylphenyl)-amide 5-(2-(2- |4H), 1.64 -1, 77 (t, 4 H). pyrrolidin-1-ylethylcarbamoyl)-pyridin-4-yloxy|-indole-1-carboxylic acid. fi; (DMSO-α) 6 ppm 10.42 (5, 1

H), 8.51 (a, 9-5.6 Hz, 1 H), 8.35 (y,

Mo M S U-8.8 Hz, 1 H), 8.17 (9, 923.8 Hz, 1 28-E rya H), 8.10 (5, 2 H), 7.98 (y, U -8.3 Hz, 441.0 o MH, o nn 1 H), 7.59 - 7.73 (t, 2 H), 7.45 - ' (3-trifluoromethylphenyl)-amide 5-(2- i t lvvit was in 83 (Я ! carbamoylpyridin-4-yloxy)-indol-1-des 5 hy H " b " carboxylic acid I C, ).

with fi; (DMSO-dv) 6 ppm 10.42 (5.1

H), 8.72 (9, 9-5.1 Hz, 1 H), 8.49 (4, and in uh Se, |9-5.6 Hz, 1 H), 8.34 (y, U -8.8 Hz, 1

N rya H), 8.17 (9, 9-3.8 Hz, 1 H), 8.10 (5, ov OM o nH tn) tov (Aug NU 76581

I" -8.0 Hz, 1 N), 7.45 - 7.54 (t, 2 N), 7.37 (a, 9-2.5 Hz, 1 N), 7.12 - 7.23 (Z-trifluoromethylphenyl)-amide 5-(2-Sto M vot nu ovecha y Z cyclopropylcarbamoylpyridin-4-GI AN ' ' shk min yloxy)-indole-1-carboxylic acid C, ). ; The same fi; (DMSO-dv) b parts/million 10.44 (bg. 85., 1 H), 8.41 - 8.54 (t, Z H), 8.16 i U. So (a, 9-3 .8 Hz, 1 N), 8.07 (5.1 N),

H M 7.87 (Bg. 8., 1 H), 7.54 (Bg. 5., 1 H), gva| o m on 7.46 (Bg. 8., 1 H), 7.26 - 7.41 (t, 2 4831

X-H), 7.17 (99, 2-6,2,1.6 HZ, 1 H), 7.06 - 7.14 (t, 1 H), 6.71 (bg. 5., 1 (Z-trifluoromethylphenyl)-amide 5-(2-H), 4.00 -411 (t, 1 H), 1.16 (a, isopropylcarbamoylpyridin-4-yloxy)- | )-6.6 Hz, 6 H ) of indole-1-carboxylic acid o (DMSO-ob) b parts/million 10.49 (5, 1 o If; H), 8.63 - 8.71 (t, 1 H), 8.52 (a , 95.8 Hu, 1 H), 8.41 (a, 9-91 Hu, 1

M M S H), 8.21 (a, 923.8 Hz, 1 H), 8.10 (5,

H p 1 n), 7.95 (y, 9U-8.3 Hz, 1 H), 7.60 (y, 28-Н| o M o nn y-8.0 Gu, 1 H), 7, 50 (y, U-2.3 Hz, 1 499.1

M ,0-H), 7.43 (a, 9-78 Hz, 1 H), 7.39 (a, (3-trifluoromethylphenyl)-amide 5-(2-(2-gin) pi ve in methoxyethylcarbamoyl )-pyridine-4-n), 6 77 (a 3 5 HC 1 n) with yloxy|-indole-1-carboxylic acid Z Av (t AN 3 28-3 38 t zn - fi; (DMSO-dv) 6 freq./million 10.50 (5, 1 and H), 8.90 (4, 9-8.3 Hz, 1 NU, 8.52 (a,

M. M still 9-5.6 Hz, 1 H), 8.40 (a, 9-8.8 Hz, 1

H r 3 |H), 8.21 (9, 9-3.5 Hz, 1 H), 8.11 (5, a o NN 1 H), 7.96 (9, 9-8.3 Hz, 1 H), 7.61 (y, 28-I 9-8.0 Hz, 1 H), 7.49 (y, y-2.3 Hz, 1 495.1 schu, H), 7.44 ( 9, 9-7.6 Hz, 1 NU, 7.37 (a, 92.5 Hz, 1 H), 7.10-721 (t, 2 H), (3-trifluoromethylphenyl)-amide 5-(2 - 6.78 (y, 9-3.5 Hz, 1 H), 4.32 -4.45 cyclobutylcarbamoyl-pyridine-4- (t, 1 H), 2.09 - 2.21 (t, 4 H ), 1.59 yloxy)-indole-1-carboxylic acid -1.71 (t, 2 N). o (DMSO-y6) b parts/million 10.46 (bg. m X 5., 1 N) , 8.80 (i, 9-61 Hz, 1 N), 8.51

I r IF; (a, 9-5.6 Hz, 1 H), 8.38 (y, 9-91 Hz,

M M Seu 11 H), 8.18 (9, 9-33 Hz, 1 H), 8110

H Hm (5, 1 NU, 7.96 (a, 9-7.8 Hz, 1 H), 2843 | OM o o n 7.62 (i, 9-8.0 Hz, 1 H), 7, 51 (a, 513.1

Kit y-2.3 Hz, 1 H), 7.46 (9.9-71 Hz, 1 (3-trifluoromethylphenyl)-amide 5-(2-(3- tbo(t o) in ut 1 methoxypropylcarbamoyl) -pyridine-4-n) C 26v-- C 37 (t in n) 322 (5 C yloxy|-indole-1-carboxylic acid B I I shk I

E sh- "So-x (acetonitrile-az) b frequent./million 8.84

M. M C (5, 1 H), 8.49 (a, U-6.06 Hz, 1 H), , rya with 18.08 (5, 1 H), 7.87 (5, 1 H) . H), 7.01 / -7.07 (t, 2 H), 6.61 (5, 1 H), 3.70 (3-trifluoromethylphenyl)-amide 4-fluoro-5- (5, C H) , 5.28 - 3.34 (t, Z H), 2.66 (g-(methoxymethyl-carbamoyl)-pyridine- (5, Z H).

E about (6)

With (acetonitrile-az) b frequency/million 8.83

M. 22 M SE (Bg. 5, 1 N) 8.36 (a, U-5.81 Hz, 1 N),

H r 3 17.97 (5.2 N), 7.77 (d, 9U-8.34 Hz, 1 28-I OM o nn H), 7.53 (y, 9-8.08 Hz, 2 H), 7.44 (a, 486.9

M 7.58 Gu, 1 H), 7.38 (y, 9-2.53 1 4-fluoro-2-methyl-(3-trifluoromethyl-ni C, t pov H ! phenyl)-amide 5-(2 -methylcarbamoyl- she ' she ' And pyridin-4-yloxy)-indole-1-carboxylic acid

Example 29 (3-Trifluoromethylphenyl)-amide of 4-fluoro-5-(2-hydroxymethylpyridin-4-yloxy)-2-methylindole-1-carboxylic acid.

IS

With SoO-roya

M on o nn

The compound of example 28-K (960 mg, 1.86 mmol) is dissolved in Meon (30 ml) and cooled to 0 °C under nitrogen atmosphere with stirring. Then MavBna (392 mg, 10.4 mmol) is added and the reaction mixture is stirred at 0 "S. The reaction mixture is allowed to warm to room temperature and stirred for 1.5 h.

The reaction is stopped and concentrated under reduced pressure. The resulting foamy substance is transferred to

EODAs and add 0.5 n. Mahon. The two-phase solution is vigorously shaken and the layers are allowed to separate.

The aqueous layer is washed again with EtOAc and the combined organic substances are dried over

Mag5O", filtered and concentrated in a vacuum. The resulting crude oil is purified using

KFH. MS (IER) t/2 459.9 (M--1); "H NMR (400 MHz, chloroform-a) 5 ppm 8.39 (y, U-6.06 Hz, 1 H), 7.90 (5, 1H), 7.79 (a, 9- 7.83 Hu, 1 H), 7.66 (5, 1H), 7.56 (I, 9-7.96 Hu, 1 H), 7.45 - 7.53 (t, 2 H), 7 ... ,27 Hz, 1 N), 6.54 (5.1 N), 4.67 (5.2 N), 2.67 (5, C H).

Example 30 5-(2-(Dimethylamino)methyl)pyridin-4-yloxy)-4-fluoro-2-methyl-M-(3-trifluoromethyl)phenyl)-1H-indole-1-carboxamide .

IS

(6) sus what oyu 7

In a round-bottomed flask with a volume of 100 ml, add the compound of example 29 (865 mg, 1.88 mmol) in DCM (20 ml) and obtain a suspension. The reaction vessel is cooled to 0 °C in an ice water bath.

M5CI (300 μl, 3.85 mmol) and DIPEA (600 μl, 3.44 mmol) are added by syringe. The reaction mixture quickly becomes homogeneous, and it is heated to CT while stirring. After 2 hours the reaction is stopped and concentrated in vacuo. The resulting brown oil is absorbed in a pre-filled cartridge of 3 12 g of silica gel. The product is eluted in a gradient mode with a mixture of 0-100 95 EAs/heptane and (4-(4-fluoro-2-methyl-1-(3-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)pyridine-2 - yl)umethylmethanesulfonate MS (IER) t/2 538.9 (M--1))Y), as well as a product contained in a small amount, which is identified as 5-(2-(chloromethyl)pyridine-4- yloxy)-4-fluoro-2-methyl-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide. MS (IER) t/ 479.9 (M.--1).

In a vessel of 1-OKAM, the mixture obtained above (140 mg, 0.260 mmol) is transferred to DCM (1.5 ml) and an orange solution is obtained. Dimethylamine in Meon (2.0 M, 0.4 mL, 0.800 mmol) was added and the reaction mixture was stirred at RT. After standing overnight, the reaction mixture is loaded into a pre-filled cartridge with 12 g of silica gel. The rest of the solvent is removed by blowing through a layer of high-pressure air. The desired product is eluted with a mixture of 0-10 95 Meon/DxHmM in a gradient mode from a silica gel cartridge and 5-(2- ((dimethylamino)methyl)pyridin-4-yloxy)-4-fluoro-2-methyl-M-(3 -"trifluoromethyl)-phenyl)-1H-indole-1-carboxamide. MS (ER) t/2 486.9 (M--1); "H NMR (400 MHz, DMSO-dv) b freq./million 11.01 (5, 1 H), 8.37 (a, y-4.55 Hz, 1 H), 8.11 (5, 1 H), 7.91 (a, 9U-7.33 Hz, 1 H), 7.67 (Ii, 9-7.96 Hz, 1 H), 7.55 (a, 9U-8.59 Hz, 2 H), 7.17 (a, 2-7.83 Hz, 1 H), 6.79 - 6.94 (t, 2 H), 6.66 (5, 1 H), 3.46 (5 , 2 H), 2.59 (5, C H), 2.13 (5, 6 H).

Example 31

Z31-A. Tert-butyl ether of /4-oxo-4,5,6,8-tetrahydro-ZN-pyridoY3,4-4|pyrimidine-7-carboxylic acid. (in)

CO

In MAO mot tk 7-Benzyl-5,6,7,8-tetrahydro-ZN-pyridoyi3,4-d|pyrimidin-4-one (publication Oga. Rhos. Ve5. YuOyem. 2005, 9, 80) (36, 9 g, 153 mmol) and BOC anhydride (40.1 g, 184 mmol) are transferred into MeOH (600 mL). The vessel is purged with argon and palladium on charcoal (10 95 wt/wt; wet) (5.0 g) is added. Then the contents are stirred in a hydrogen atmosphere (1 atm.) for 18 hours. Then the suspension is filtered through celite? and the resulting solution is concentrated and the desired compound is obtained. MS (IER) t/2 252.0 (M.n1). 31-8. Tert-butyl ether of 4-chloro-5,8-dihydro-6H-pyridoyi3,4-4|pyrimidine-7-carboxylic acid.

SI axis xx M (F) av tk

Triphenylphosphine (17.3 g, 66.1 mmol) is added to a solution of tert-butyl ether of 4-oxo-4,5,6,8-tetrahydro-ZN-pyridoyi3,4-4|Ipyrimidine-7-carboxylic acid (8, 30 g, 33.0 mmol), CCi. (9.6 mL, 99 mmol) and 1,2-dichloroethane (250 mL). The solution is heated at 70 "C for 2.5 hours. The solution is concentrated in a vacuum to a volume equal to approximately 50 ml. Then the contents of the flask are filtered through a layer of silica gel eluting with a mixture of 60 95 EIOAc/heptane. The residue after concentration is further purified using a flash -chromatography (10-30 96 EtOAc/heptane) and obtain the desired compound.

MS (IER) t/2 270.0 and 272.0 (М-А1); "H NMR (400 MHz, SOSI") b freq./million 8.79 (5.1 N), 4.65 (5.2 N), 3.74 (I, 9-5.8 Hz, 2 N ), 2.87 (I, Y-5.8 Hz, 2 H), 1.49 (5, 9 H). 31-06. Tert-butyl ether 4-(1H-indol-5-yloxy)-5 ,8-dihydro-6H-pyrido|3,4-4|pyrimidine-7-carboxylic acid.

Ge) av;

M. M

N

Ma I

To a solution of 4-chloro-5,8-dihydro-6H-pyrido-3,4-4|pyrimidine-7-carboxylic acid tert-butyl ether (5.46 g, 20.2 mmol), 5-hydroxyindole (3.50 g , 26.3 mmol) and SNISM (100 mL) add DBU (4.0 mL, 26.3 mmol). Then the mixture is heated at 50 "С for 4 h. Then the solvent is removed in vacuo and the residue is purified with the help of KFC (10-50 956 EOAc/heptane) and the desired compound is obtained. MS (IER) t/2 367.1 (M.n1 ).

The following compounds are obtained by a similar method. 31-00. 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5,8-dihydro-6H-pyridoyl3,4-a|pyrimidine-7-carboxylic acid tert-butyl ether.

IS

(c) se СОо-

Mo M

N

M oo

MS (ER) t/2 399.0 (M-n1) 31-E. Tert-butyl ether of 4-(4-fluoro-1H-indol-5-yloxy)-5,8-dihydro-bH-pyridoi|3,4-4|pyrimidine-7-carboxylic acid.

IS

(c) tva;

MO 2 M

N

Ma I

MS (ER) t/2 385.1 (M-n1)

Z31-E. Tert-butyl ether of 4-(6b-fluoro-1H-indol-5-yloxy)-5,8-dihydro-6H-pyrido|3,4-4|pyrimidine-7-carboxylic acid. you

M

OM KZ sa - (c) va;

M

And N

MS (ER) t/2 385.0 (M-n1)

Example 32

Tert-butyl ether of 4-(2-methyl-1H-indol-5-yloxy)-5,8-dihydro-6H-pyridoyl3,4-4|pyrimidine-7-carboxylic acid. (c) ee C-

M. M

N

Ma I

When stirring to a solution of tert-butyl ether 4-oxo-4,5,6,8-tetrahydro-ZN-pyrido|3,4-

α|pyrimidine-7-carboxylic acid, the compound of example 31-A (300 mg, 1.2 mmol) in ACN (5 ml) is added

RUVOR (800 mg, 1.55 mmol) and DBU (0.2 ml, 1.43 mmol). In 20 minutes. add 2-methyl-1H-indol-5-ol (211 mg, 1.43 mmol). Then the mixture is stirred at room temperature for 16 hours. The reaction mixture is then concentrated under reduced pressure and the residue is dissolved in EIOAc and washed with water and brine. The organic layer is dried over sodium sulfate, concentrated under reduced pressure. The residue is purified by KFC (EOAc/heptane from 0 to 40 95) and the desired compound is obtained. MS (IER) t/2 381.0 (M--1).

Example 33 33-А. Tert-butyl ether of 4-11-(2-fluoro-5-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-5,8- dihydro-6bH-pyrido|3,4-4Y|pyrimidine-7-carboxylic acid. m. o ES vav;

M. u

M (in; N E

J

Sodium hydride (0.025 g, 0.614 mmol, 6095 in mineral oil) is added to a solution of tert-butyl ether 4-(1H-indol-5-yloxy)-5,8-dihydro-6H-pyridoY3,4-4|Ipyrimidine-7 -carboxylic acid, the compound of example 31-C (0.150 g, 0.409 mmol) and THF (5 ml) at 0 "C. After 20 min. add 2-fluoro-

B-(trifluoromethyl)phenyl isocyanate (0.168 g, 0.819 mmol). After another 1 hour. the contents of the flask are poured into a saturated aqueous solution of ManHCO3 (25 ml) and extracted with EtOAc (3x25 ml). The combined organic layers are then dried (Mag2505), filtered and concentrated. Then, the crude residue is purified by KFC (20-50 956 EtOAc/heptane) and the desired compound is obtained. MS (ER) t/2 5721 (M-n1). 33-88. (2-Fluoro-5-trifluoromethylphenyl)-amide /5-(5,6,7,8-tetrahydropyrido|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

E.S

Ge) Z vav;

M. and u

M (in; N E

N

TFC (1 ml, 13.0 mmol) was added to a solution of tert-butyl ether 4-(1-(2-fluoro-5-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-5,8-dihydro-6H-pyridoyl) ,4-4|pyrimidine-7-carboxylic acid (0.125 g, 0.219 mmol) and DCM (2.5 mL). After 1 h, the solution was concentrated in vacuo. The residue was transferred to MeonH and neutralized to pH 7 by adding MNAOH and the solution purified by semi-preparative HPLC (C18; 10-100 95 ACN/HgO with the addition of 0.195 MNAOH) and obtain (2-fluoro-5-trifluoromethylphenyl)-amide 5-(5,6,7,8-tetrahydropyridoyiZ3,4-4| pyrimidine-4-yloxy)-indole-1-carboxylic acid. MS (IER) t/2 472.1 (M--1); "H NMR (400 MHz, DMSO-α) b parts/million 8.40 (5, 1 N), 8.25 (a, 9-8.8 Hz, 1 N), 8.07 (a, 9U-3.8 Hz, 1 N), 8.03 - 8.07 (t , 1 N), 7.67 - 7.75 (t, 1 N), 7.56 - 7.64 (t, 1 N), 7.45 (9, 9-2.5 Hz, 1 N), 7.11 (yes, 9-9.0, 2.4 Hz, 1 N), 6.79 (a, U-3.5 Hz, 1 N), 3.83 (5.2 N), 3, 04 (i, y-5.8 Hz, 2 N), 2.73 (I, 9-5.6 Hz, 2 N).

The following compounds are obtained by a similar method.

OT syuyuvnnnnnnnia 100 nanny TD still kerosene (DMSO-ov) b frequent./million 10.43 (5, ee If; Z 1 H), 8.54 (5, 1 H), 8.30 (4, 9-88

M. M Hz, 1 N), 8.15 (a, 9-35 Hz, 1 N), ra 8.11 (5, 1 N), 7.98 (a, U-8.3 Hz, 1 33 -60 Mo and H), 7.65 (I, 9U-8.0 Gu, 1 H), 7.44 - 454.0

H 7.53 (t, 2 H), 7.14 (da, 2-9.0, 2,4 (3-trifluoromethylphenyl)-amide 5-(5,6,7,8- peone) 45 (a n5 and M), tetrahydropyridoyi3,4-4|pyrimidine-4-ni C00 (1-58 g of n) c, yloxy)-indole-1-carboxylic acid Sho ' "1 C, "

about EzS

Ma If; E (DMSO-dv) b parts/million 10.38 (bg. (and 5., 1 N), 8.43 (5.1 N), 8.26 (and,

M M 3-8.8 Hz, 1 H), 8.06 -8.16 (t, 2 rya H), 7.95- 8.05 (t, 1 H), 7.57 (Her, 33- 0 M o nn 99.7 Hz, 1 N), 7.46 (y, 9-2.3 Hz, 472.0

H 1 H), 7,12 (ad, 20-9,0,2,4 HC, 1 H), (4-fluoro-3-trifluoromethylphenyl)-amide 5- | 6.80 (a, 9U-3.3 Hz, 1 H), 3.93 (5,2 (5,6,7,8-tetrahydro-pyridoyi3,4-H)U, 3.14 (, 9- 5.9 Hz, 2 H), 2.79 (Y, d9|Ipyrimidin-4-yloxy)-indole-1- 95.7 Hz, 2 H). carboxylic acid

Well, what; he X (MeOr) 5 ppm 8.38 (5, 1 H), 8.13 (a, U-9.09 Hz, 1 H), 8.06 (5, 1

M M H), 7.89 (a, U-8.34 Hz, 1 H), 7.94 38-E rya (a, 9-3.79 Hz, 1 H), 7.58 (i, 9U -7.96 4719

M o nn Hz, 1 N), 7.45 (a, 9-7.83 Hz, 1 N), "

H 7.19 (t, 1 H), 6.82 (a, 9U-3.79 Hz, 4-fluoro-(3-trifluoromethylphenyl)-amide 5- | 1 H), 3.96 (5, 2 H ), 3.19 (i, 9-5.94 (5,6,7,8-tetrahydropyridoi|3,4- HZ, 2 H), 2.91 (i, 9U-5.68 Hz, 2 H) d9|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid o what;

There is If; (meO0b) 5 parts/million 8.39 (5, 1 N), 8.19 (a, 9U-11.62 Hz, 1 N), 8.05 (5,

M M 1 H), 7.95 (y, 9U-3.54 Hz, 1 H), y re 7.90 (9, 9-8.34 Hz, 1 H), 7.58 (y, 33- E M o n 97.96 Hz, 1 N), 7.45 (y, 9-7.83 471.9

H Hz, 1 H), 7.50 (a, 9-7.58 Hz, 1 H), b-fluoro-(3-trifluoromethylphenyl)-amide 5-|6.75 (a, 923.79 Hz, 1 H), 3.96 (5.2 (5,6,7,8-tetrahydropyridoi|3,4- H), 3.19 (Y, 9U-5.94 Hz, 2 H), 2.91 d9| Ipyrimidin-4-yloxy)-indole-1-(Y, Y-5.56 Hz, 2 H). carboxylic acid

I WOULD. is c 5 5 (meorb) 5 parts/million 8.38 (5.1 N),

M. and M 8.18 (a, 9-11.37 Hz, 1 N), 8.04

E rya (aa, 9U-6.19, 2.65 Hz, 1 H), 7.92 (a, 93.79 Hz, 1 H), 7.95 (bBg. 5., 1 H), 33- a and o nH 7.50 (a, U-7.58 HC, 1 H), 7.33 - 489.9 b-fluoro-(4-fluoro-3-trifluoromethylphenyl)- TZ (t, 1 NU, 6 ... ,4-hy 2 NU 2914 4-5568 11. 2 H d9|Ipyrimidin-4-yloxy)-indol-1-B, ), 2.91 (i, ' B, ). carboxylic acid o ES

There is If; (DMSO-av) b freq./million 10.53 (Bu. ! 5., 1 N), 8.40 (5.1 N), 8.26 (i,

MME y-8.8 Hz, 1 H), 8.09 (y, 9-3.8 Hz, rya 1 H), 7.83-7.94 (t, 2 H), 7.46 ( a, 33-N M o nn u-2.5 Hz, 1 N), 7.39 - 7.45 (t, 1 472.0

H H)U, 7.13 (ad, 9-9.0,2.4 Hz, 1 H), (3-fluoro-5-trifluoromethylphenyl)-amide 5-|6.81 (a, 9U-3, 8 Hz, 1 H), 3.82 (5.2 (5,6,7,8-tetrahydropyridoi|3,4- H), 3.04 (I, 9-5.68 Hz, 2 H), 2 .73 (Y, a|pyrimidin-4-yloxy)-indole-1-y-5.7 Hz, 2 H). of carboxylic acid pe o x (DMSO-yv) b parts/million 10.22 (bBg. ci r M 5., 1 N), 8.40 (5, 1 N), 8.24 (j,

X SE, y-8.8 Hz, 1 H), 8.08 (y, 9-3.5 Hz,

M 1 H), 7.89 - 8.00 (t, 1 H), 7.64 - 38 M On 7.74 (t, 1 H), 7.36 - 7.53 (t, 2 472.0

I I H), 7.12 (ad, 9-9.0,2.4 Hz, 1 H), (g-fluoro-3-trifluoromethylphenyl)-amide 5- 6.80 (4, 9U-3.5 Hz, 1 H), 3.83 (5.2 (5,6,7,8-tetrahydropyrido(3,4-H), 3.04 (i, 9-5.8 Hz, 2 H), 2, 73 (i, a|pyrimidin-4-yloxy)-indole-1-9-5.6 Hz, 2 N) carboxylic acid o ES is If; SI (DMSO-sv) b parts/million 10.43 ( bg. ! 5., 1 H), 8.40 (5.1 H), 8.26 (y,

M M 9-91 Hz, 1 H), 8.22 (a, 9-2.8 Hz, 1 rya H), 8.09 (a, 9U-3.8 Hz, 1 H), 8.00 ( a, 33-/ M o n 1 N), 7.75 (a, 9-8.8 Hz, 1 N), 7.44 488.0

H -7,A8 (t, 1 H), 7.08 - 7.16 (t, 1 (4-chloro-3-trifluoromethylphenyl)-amide 5- |H), 6.79 (a, 9U-3, 5 Hz, 1 H), 3.82 (5, (5,6,7,8-tetrahydropyrido!Y3,4- 2 H), 3.03 (I, 9-5.8 Hz, 2 H), 2 .72 a|pyrimidin-4-yloxy)-indole-1- (Her, U-56 Hz, 2 H). carboxylic acid can; ee If; (DMSO-ov) b frequency/million 8.40 (5.1

M. and M H), 8.28 (a, U-8.8 Hz, 1 H), 8.09 (a, as 93.5 Hz, 2 H), 7.84 (a, 9U-8, 6 Hz, 1

H), 7.68 (a, 9-7.8 Hz, 1 H), 7.45 (a,

Z3K and her y-2.5 Hz, 1 H), 70 (da,9-9,0.24 | 7880 (2-chloro-5-trifluoromethylphenyl)-amide 5- Hz, 1 Nu, 6.78 ( y, 23.5 Hz, 1 n), : : 3.84 (5, 2 H), 3.05 (Hii, 9U-5.8 Hz, 2 (5,6,7,8-tetrahydropyridoi|3, 4-H), 2.74 (4-57 Hz, 2 M) d9|Ipyrimidin-4-yloxy)-indol-1- b by, TC, and carboxylic acid mo what; t t SU (meob) b chast. /million 8.36 (5.1 N),

М. ), 7.46 (a, 9-8.59 Hz, 1 N), 7.27 (a,

ZV. and he 9-1.77 Hz, 1 H), 6.99 (aa, 9-9.09,| 7579 2-methyl-(3-trifluoromethylphenyl)-amide 5- 221 Hz, 1H), 6.44 ( 5, 1 H), 3.94 : : (5.2 H), 3.17 (II, 95-5.94 Hz, 2 H), (5,6,7,8-tetrahydro-pyridoyiY3,4- 2.85-2.89 (t, 2 H), 2.61 (5, C H) d9|Ipyrimidin-4-yloxy)-indole-1-' ' ' shk ' y carboxylic acid

Well, what; ha X (DMSO-sv) b part./million 10.99 (5.1 N), 8.57 (5.1 N), 8.12 (5.1 N),

M M 7.92 (a, 9-6.57 Hz, 1 H), 7.64-7.69 38-M rya (t, 1 H), 7.53 (a, U-8.84 Hz, 2 H), 485 8

M o nn 7.15 (yes, U-8.84, 7.83 Hz, 1 H), '

H 6.62 (5, 1 H), 4.33 (c, 2 H), 5.51 (i, 4-fluoro-2-methyl-(3-4-6.06 Hz, 2 H), 3 ,05 (5.2 N), trifluoromethylphenyl)-amide 5-(5,6,7,8- 2.59 (in, 3 H), 1.75 (5, 1 N). tetrahydropyridoyi3,4-4| pyrimidine-4-yloxy)-indole-1-carboxylic acid

IS

E.S

The most common (meob) 5 parts/million 8.37 (5.1 N), p 8.07 (aa, U-6.32, 2.78 Hz, 1 N),

M U. 7.90 (bg. 5., 1 H), 7.49 (d, -8.84

Y M Gu, 1 H), 7.39 (Her, U-9.60 Hz, 1 H), 33-M M o H 7.07 (ad, 9-8.72, 7.45 Hz, 1 H ), 5О3

H 6.52 (5.1 H), 3.96 (5.2 H), 3.19 (i, 4-fluoro-2-methyl-(4-fluoro-3-9-5.94 Hz, 2 H), 2.90 (Y, 9U-5,43 trifluoromethylphenyl)-amide 5-(5,6,7,8-HC, 2 H), 2.61 (5, C H). tetrahydropyridoyY3,4-4 |pyrimidin-4-yloxy)-indole-1-carboxylic acid

Example 34 (3-Trifluoromethylphenyl)-amide of 5-(7-acetyl-5,6,7,8-tetrahydropyrido|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

E.S. o) From the old school;

M. 22 u

M

M o nn o"

Acetic anhydride (0.05 ml, 0.496 mmol) was added to a solution of the compound of example 33-C (0.150 g, 0.331 mmol), EBM (0.14 ml, 0.792 mmol) and DXM (5 ml). After 0.5 hours the solution is concentrated and then purified using semi-preparative HPLC (10-90 965 ACN/HgO with the addition of 0.1 95 MNAOH) and the desired compound is obtained. MS (ER) t/2 496.0 (M--1); "H NMR (400 MHz, DMSO-av) b freq./million 10.38 (5, 1 H), 8.45 - 8.53 (t, 1 H), 8.27 (a, 9-91 Gu , 1 N), 8.12 (a, 9-38 Hz, 1 N), 8.10 (5, 1 N), 7.97 (a, 9-8.8

Hz, 1 H), 7.65 (I, 9-81 Hz, 1 H), 7.50 (a, U-7.8 Hz, 1 H), 7.47 (a, 9-23 Hz, 1 H), 7.14 (ad, 2-9.0, 2.4 Gu, 1

H), 6.80 (9, 9-3.5 Hz, 1 H), 4.63 (5, 2 H), 3.81 (I, 9-5.9 Hz, 2 H), 2.93 (Her, 9-5.7 Hz, 2 H), 2.16 (5, Z H).

Example 35 (3-Trifluoromethylphenyl)-amide of 5-(7-methanesulfonyl-5,b,7,8-tetrahydro-pyridoyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

Es o) With fi;

M. 2 U

M

M o nn -3 y: (6)

Methanesulfonyl chloride (0.04 ml, 0.496 mmol) was added to a solution of the compound of Example 33-C (0.150 g, 0.331 mmol), EBBM (0.14 ml, 0.792 mmol) and DXM (5 ml). After 0.5 hours the solution is concentrated and then purified using semi-preparative HPLC (10-90 95 ACN/HgO with the addition of 0.1 95

MNAOH) and get the desired compound. MS (ER) t/2 532.0 (M--1); "H NMR (400 MHz, DMSO-av) b freq./million 10.39 (5.1 H), 8.51 (5.1 H), 8.28 (y, U-9.1 Hz, 1 H), 8.13 (а, 9У-3.8 Hz, 1 H), 8.10 (5, 1 H), 7.97 (а, у3-8.6 Hz, 1 H), 7.65 (1, 9-81 Hu, 1 H), 7.51 (5, 1 H), 7.49 (a, 9-23 Hz, 1 H), 7.15 (aa, U-9,0,24 Hz, 1 N), 6.81 (9, 9U-3.3 Hz, 1 N), 4.39 (5, 2 N), 3.58 (I, 9-5.9 Hz, 2 N), 3.06 (5, Z H), 2.97 (I, 9-5.7 Hz, 2 H).

Example 36

Ethyl ether of 4-(/1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-5,8-dihydro-6H-pyridoi3,4-a|pyrimidine-7-carboxylic acid.

E.S

Mao and -sh in;

M. 2 U.

M

M o nn 07 o.

Ethyl chloroformate (0.06 ml, 0.661 mmol) was added to a solution of the compound of Example 33-C (0.200 g, 0.441 mmol), pyridine (0.11 ml, 1.32 mmol) and DCM (5 ml). After 0.5 hours the solution is concentrated and then purified using semi-preparative HPLC (10-90 965 ACN/HgO with the addition of 0.1 95 MNAOH) and the desired compound is obtained. MS (ER) t/2 526.1 (M--1); "H NMR (400 MHz, DMSO-av) b frequency/million 10.38 (5, 1 H), 8.49 (v, 1 H), 8.27 (a, U-8.8 Hz, 1 H), 8.12 (a, U-3.8 Hz, 1 H), 8.10 (5, 1 H), 7.97 (a, 9-8.3 Hz, 1 H), 7.65 (her, 9-81 Hz, 1 H), 7.50 (a, 9-78 Hz, 1 H), 7.47 (a, 9-2.3 Hz, 1 H), 7.14 (aa, 2-8.8, 2.3 Hz, 1 H), 6.80 (a, 9-3.5 Hz, 1 H), 4.57 (Bg. 5., 2 H), 4.12 (a , 9-71 Hz, 2 H), 3.76 (I, 9-5.4 Hz, 2 H), 2.86 (I, 9-5.6 Hz, 2 H), 1.24 (and U -71 Hz, Z H).

Example 37 37-А. (3-Trifluoromethylphenyl)-amide /5-(7-ethyl-5,6,7,8-tetrahydropyrido|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

Eh, b

Av) z - vshf;

Mo U.

M r o nn

To a solution of the TFC salt of the compound of example 33-C (0.720 g, 1.59 mmol), acetaldehyde (0.18 ml, 3.18 mmol), EM (0.44 ml, 3.18 mmol) and DHE (10 ml ) add sodium triacetoxyborohydride (0.673 g, 0.3.18 mmol). After 1 hour the suspension is poured into a saline solution (50 ml) and extracted with DCM (3x50 ml). The combined organic layers were then dried (Mag25O4), filtered and concentrated. The residue is purified using semi-preparative HPLC (10-90 95 ACN/HgO with the addition of 0.1 95 MNAOH) and the desired compound is obtained. MS (IER) t/2 482.2 (M--1); "H NMR (400 MHz,

DMSO-dv) 6 ppm 10.38 (Bg. 5., 1 N), 8.42 (5, 1 N), 8.28 (a, 92-91 Hz, 1 N), 8.11 (a, U-3.8 Hz, 1 H), 8.10 (5, 1 H), 7.96 (9, 9-91 Hz, 1 H), 7.63 (I, 9-8.0 Hz, 1 H), 7.48 (a, 9-78 Hz, 1 H), 7.46 (a, 9-2.5 Hz, 1 H), 7.13 (aa, U-9.0, 2.4 Hz, 1 N), 6.78 (a, U-3.8 Hz, 1 N), 3.57 (5.2 N), 2.74 - 2.87 (t, 4 N), 2.59 (4.9-7.2 Hz, 2 N), 1124.9-72 Hz, Z H).

The following compounds are obtained by a similar method.

SHCI Structure/chemical name "H' NMR (400 MHz) Mo A t/h

Eh, b

MO z z E (y (meOb) 5 parts/million 8.39 (5.1 N), 8.33

M M (a, 9-91 Hz, 1 N), 8.04 (ai, 9U-6.3, 2.8 about Hz, 1 N), 7.89 - 7.95 (t, 2 N), 7.40 (a,

M n 9-23 Hz, 1 H), 7.36 (I, U-9.6 Hz, 1 H), 37-V r 7.10 (44, 9-90, 2.4 Hz, 1 H) . , 2 H), 2.87 - 2.92 (t, 2 H), 2.71 (9, amide 5-(7-ethyl-5,6,7,8-tetrahydro-|9-7.2 Hz .

E,b fe, Z t s IF; With (MeOb) 5 ppm 8.53 (5.1 N), 8.36

M. 2 M (a, 9-91 Hz, 1 H), 8.07 (5, 1 H), 7.96 (a, p 3-38 Hz, 1 H), 7.90 (a, 9- 81 Hz, 1 N),

M o y 7.58 (I, U-8.0 Hz, 1 H), 7.40 - 7.48 (t, 2 37-60 NO, 7.13 (ad, 9U-9.0, 2, 4 Hz, 1 H), 6.75 (a, 496.1 and 3-3.8 Hz, 1 H), 4.46 (Bg. 5., 2 H), 3.70 (3-trifluoromethylphenyl)- amide 5-(7- what 97 (so I bo Well I t 85 propyl-5,6,7,8-tetrahydropyridoiZ,4- d-7 5G z u shi ' shi ' 9|Ipyrimidin-4-yloxy)-indole -1- Z, I carboxylic acid

E.S

Ge) Z vav; (meob) 5 parts/million 8.53 (5.1 N), 8.36

M M (a, 9-91 Hz, 1 H), 8.07 (5, 1 H), 7.96 (a, o 3-3.8 Hz, 1 H), 7.89 (y, 9- 88 Hz, 1 N),

M Hn 7.58 (I, U-8.0 Hz, 1 H), 7.38 - 7.47 (t, 2

Zo A NU, 7.12 (ad, 9-9.1,2.3 Hz, 1 N), 6.754, by 3-3.8 Hz, 1 N), 4.45 (Bg. 5.,2 N ), 3.77 - (3-trifluoromethylphenyl)-amide 5-(7- |3.87 (t, 1 H), 3.67 (Bg. 5., 2 H), 3.25 (Br. isopropyl 5,6,7,8- 5,2 N), 1,50 (a, U-6,6 Hz, 6 N). acid still ES is se If; (MeOb) 5 ppm 8.39 (5.1 N), 8.33

M. 22 M (a, 9-91 Hz, 1 H), 8.06 (5, 1 H), 7.93 (y, cancer 3-3.5 Hz, 1 H), 7.90 (y, 9-9.9 Hz, 1 N), 7.57 (1, 9U-8.0 Hz, 1 N), 7.44 (a, 9-71 Hz,

ZE and on 1 N), 7.40 (9, 2-2.3 Hz, 1 N), 7.11 (а9, 468.0 . . 9-9.0, 2.4 Hz, 1 N), 6.74 (a, 9-3.5 Hz, 1 (Z-trifluoromethylphenyl)-amide 5-(7- H), 3.64 (c, 2 H), 2.98 ( y-5.8 Hz, 2 H), methyl-o5,6,7,8-tetrahydropyrido!|3,4- 2.83 sh 2.90 (t, 2 H), 2.54 (in, C H). 9|Ipyrimidine-4 -yloxy)-indole-1-carboxylic acid

IS

E.S

IF) Z

E Z r Co (meOb) 5 parts/million 8.38 (5.1 N), 8.07

M M (5, 1 H), 7.87 (y, U-8.08 Hz, 1 H), 7.59 (y,

Hm 3-8.08 Hz, 1 H), 7.48 (t, 2 H), 7.06 (aa, 37-E M o n u-8.72, 7.45 Hz, 1 H), 6 .51 (5.1 N), 3.68 513.2

and 7.07 Hz, 2 (3-trifluoromethylphenyl)-amide 5-(7-|H), 2.61 (5, З H), 1.23 (I, 9U-7.33 Hz, З Н) ethyl- 5,6,7,8-tetrahydropyrido3,4-α9|pyrimidin-4-yloxy)-4-fluoro-2-methylindole-1-carboxylic acid

Example 38 38-А. (3-Trifluoromethylphenyl)-amide 5-(6-(4-aminopiperidin-1-ylmethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid.

E.S

Ge) Z va;

M. and u

In (c) N

MH,

To a solution of /6-(1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyrimidin-4-ylmethyl ether of methanesulfonic acid, compound of example 18-B (0.6 g, 1.19 mmol) in THF (8 mL) and DMF (8 mL) was added tert-butylpiperidin-4-ylcarbamate (0.713 g, 3.56 mmol), followed by DIPEA (0.62 mL, 3.56 mmol) and sodium iodide (0.534 g, 3, 56 mmol). The solution is stirred at RT for 2.5 h and then partitioned between EOAc and saturated aqueous MnSOO 2 . The layers are separated and the organic layer is further washed with brine and then dried over Mg 5 O", filtered and concentrated. After concentration, the residue is purified with the help of KFH (20-80 95

EtOAc/heptane). The product is then treated with 50,956 TFC in DCM at RT for 1 hour.

After concentration, the residue is purified using semi-preparative HPLC (20-55 95 ACN/HgO with the addition of 0.1 95 MNAOH) and the desired compound is obtained. MS (ER) t/2 511.1 (Me1); "H NMR (400

MHz, DMSOSO-av) 6 parts/million 8.66 (5, 1 N), 8.29 (a, 9-9.0 Gu, 1 N), 8.16 (a, U-3.7 Hz , 1 H), 8.11 (5, 1 H), 7.98 (a, 9-8.2 Hz, 1 H), 7.65 (I, 9U-8.0 Gu, 1 H), 7 .46 - 7.54 (t, 2 N), 7.16 (yes, U-8.9, 2.3 Hz, 1 N), 7.03 (5.1 N), 6.80 (a, 9-3.7 Hz, 1 N), 3.57 (5.2 N), 2.74 - 2.90 (t, Z H), 2.11 (1, U-10.68 Hz, 2 N ), 1.78 (a, U-124 HC, 2 N), 1.91 -1.51 (t, 2 N). 38-85. (3-Trifluoromethylphenyl)-amide 5-(6-(4-acetylaminopiperidin-1-ylmethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid.

E.S

Ge) Z

Su

M. 2 u

In about N

Min)

To a solution of 5-(6-(4-aminopiperidin-1-ylmethyl)-pyrimidin-4-yloxy|indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide (0.159 g, 0.312 mmol) in THF (2 ml) and DCM (2 mL) at 0 °C were added DIPEA (0.163 mL, 0.935 mmol) and acetyl chloride (29 μL, 0.405 mmol). The reaction mixture was stirred at 0 °C for 2.5 h and then partitioned between EtOAc and saturated aqueous solution

Mans Soz. The layers are separated and the organic layer is further washed with brine and then dried over NaCl5Ox. After concentration, the residue is transferred to THF (8 ml) and MeOH (8 ml) and at RT for 0.5 h. treated with K2СО3. Then the mixture is filtered and concentrated. Then the residue is purified using semi-preparative HPLC (20-50 95 ACN/H2O with the addition of 0.1 95

MNAOH) and get the desired compound.

MS (IER) t/2 553.2 (M--1); "H NMR (400 MHz, DMSO-dv) b freq./million 8.66 (y, 9U-1.0 Hz, 1 H), 8.49 - 8.61 (t, 1 H), 8.12 (0.9-3.5 Hz, 1 N), 8.04 (5, 1 N), 7.69 - 7.83 (t, 2 N), 7.37 - 7.51 (t, 2 N ), 7.14 - 7.26 (t, 1 H), 7.04 (y, 9-91 Gu, 1 H), 6.96 (5, 1 H), 6.55 - 6.63 (t , 1 H), 3.44 - 3.59 (t, With H), 2.72-2.82 (t, 2

H), 2.06 - 2.18 (t, 2 H), 1.76 (5, With H), 1.63 -1.73 (t, 2 H), 1.27 -1.42 (t , 2 N), 1.24 (5.1 N).

The following compounds are obtained by a similar method. 38-Sab. (3-Trifluoromethylphenyl)-amide /5-16-(4-(cyclopropanecarbonylamino)-piperidin-1-ylmethyl|-pyrimidin-4-yloxy)-indole-1-carboxylic acid. se; ES vv;

He is 22 years old

In about N

MN

(c) h

MS (IER) t/»2 579.1 (M-e-1); "H NMR (400 MHz, DMSO-dv) 6 ppm 8.66 (5.1 H), 8.29 (a, 9U-8.8 Hz, 1

H), 8.14 (a, 9U-3.5 Hz, 1 H), 8.10 (5, 1 H), 7.96 (Her, 9-8.6 Hz, 2 H), 7.65 (I, 9U-8.0 Hz, 1 N), 7.47 - 7.53 (t,2 N), 7.17 (а9, 9-9.0, 2.4 Hz, 1 N), 7 .04 (5, 1 H), 6.81 (a, 9U-3.5 Hz, 1 H), 3.48 - 3.62 (t, C H), 2.80 (a, 9-11, 1 Hz, 2 N), 2.14 (, 20-10.7 Hz, 2 N), 1.72 (a, 90-124 Hz, 2 N), 1.47 -1.57 (t, 1 N ), 1.33-1.48 (t, 2 N), 0.55 - 0.68 (t, 4 N).

Example 39 (3-Trifluoromethylphenyl)-amide of 5-16-(4-methanesulfonylaminopiperidin-1-ylmethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid.

E.S

Ge) Z

Su

M. 2 u

In about N

MN

82 oo

It is obtained in the same way as described in example 35. MS (IER) t/2 589.1 (M--1); "H NMR (400 MHz,

DMSO-dv) b parts/million 8.66 (a, 9U-1.0 Gu, 1 H), 8.33 - 8.58 (t, 1 H), 8.12 (a, 9U-3, 8 Hz, 1 N), 8.05 (5, 1 N), 7.74 - 7.93 (t, 1 N), 7.36 - 7.60 (t, 2 N), 7.01 - 7 .13 (t, 2 H), 6.99 (v, 1 H), 6.56 - 6.74 (t, 1 H), 3.54 (5.2

H), 3.04 - 3.21 (t, 1 H), 2.90 (5, with H), 2.72 - 2.84 (t, 2 H), 2.06 - 2.20 (t , 2 H), 1.74 -1.87 (t, 2 H), 1.36 -1.54 (t, 2 H).

Example 40 (3-Trifluoromethylphenyl)-amide of 5-I(7-(3-diethylaminopropionyl)-5,6,7,8-tetrahydropyrido3,4-a|pyrimidin-4-yloxy|-indole-1-carboxylic acid. se ;

M. 22 u

And - - ' pk

M

And a

To a solution of (3-trifluoromethylphenyl)-amide of 5-(5,6,7,8-tetrahydropyrido|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid, the compound of example 31-C (120 mg , 0.26 mmol), NATI (198 mg, 0.52 mmol),

3-diethylaminopropionic acid hydrochloride (47 mg, 0.26 mmol) was added to DIPEA (0.2 mL, 1.30 mmol) and DMF (5 mL). After stirring at CT for 2 h. the contents of the flask are subjected to distribution between

DXM and 10 95 aqueous solution of GiSi. The organic layer is separated, dried over anhydrous Mag5O4 and concentrated in vacuo. Then the residue is purified by means of semi-preparative HPLC (C18; 10-100 96 ACN/H2gO with the addition of 0.1 95 MNAOH) and the desired compound is obtained. MS (ER) t/2 581.2 (M-H1);

NMR NMR (400 MHz, Meob) b frequency/million 8.40 - 8.48 (t, 1 H), 8.33 (y, 9U-8.8 Hz, 1 H), 8.06 ( 5, 1 H), 7.94 (y, 9-3.5 Hz, 1 H), 7.89 (a, Y-8.6 Hz, 1 H), 7.57 (I, 9-81 Hz , 1 N), 7.36 - 7.47 (t, 2 N), 7.10 (ad, 2U-9.0, 2.1 Hz, 1 N), 6.74 (9, 90-3, 8 Hz, 1 N), 4.71 - 4.79 (t, 2 N), 3.85 - 4.05 (t, 2 N), 3.20 (y, 9U-5.8 Hz, 2 N ), 2.84 - 3.08 (t, 8 N), 1.23 (4, 9-71 Hz, 6 N).

Example 41 41-A. 44-P1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-5,8-dihydro-bH-pyrido!|3,44|pyrimidin-7-yl)-acetic acid tert-butyl ether. still studied EzS;

M.O. 22 u

M (6) H you (6)

A solution of (3-trifluoromethylphenyl)-amide 5-(5,6,7,8-tetrahydropyridoyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid, compound of example 33-C (250 mg, 0, 55 mmol), bromo-tert-butyl acetate (204 μL, 1.38 mmol), TEA (triethanolamine) (384 μL, 2.76 mmol) and ACN (5 mL) were stirred at room temperature. At the end of the reaction, the contents of the flask are subjected to distribution between DCM and saline solution. The organic layer is dried over anhydrous Ma»5O:, concentrated and the residue is purified by KFC (500-100 96 EOAc/heptane) to obtain the desired compound. MS (ER) t/2 568.1 (M-n1). 41-8. 14-(11-(3-Trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-5,8-dihydro-6H-pyridoy|3,4- d9|pyrimidin-7-yl)-acetic acid.

E.S

ГФ) Z vav;

M. 2 u

M (in) N

Susn (c)

A solution of tert-butyl ether 14-(1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy)|-5,8-dihydro-6H-pyridoyl3,4-4|pyrimidin-7-yl)-acetic acid ( 250 mg, 0.44 mmol), DCM (5 ml) and TFC (5 ml) were stirred at RT for 1 h. The solution is concentrated in a vacuum and purified using semi-preparative HPLC (C18; 10-100 965 ACN/HgO with the addition of 0.1 95 MNAOH) and the desired compound is obtained. MS (IER) t/» 512.0 (M--1); "H NMR (400 MHz, meor) b freq./million 8.41 (5, 1 H), 8.33 (a, U-9.1 Gu, 1 H), 8.06 (5, 1 H) , 7.93 (y, 9-3.5 Gu, 1 H), 7.89 (5, 1 H), 7.57 (I, 9-81 Hz, 1 H), 7.38 - 7.47 (t, 2 H), 7.12 (ad, 9U-9.0, 2.4 Hz, 1 H), 6.74 (a, 9-3.5 Hu, 1 H), 4.08 (5 , 2 H), 3.56 (5, 2 H), 3.26 (I, 5-61 Hz, 2 H), 3.07 (Y, 3-5.7 Hz, 2 H). 41-06 (3-Trifluoromethylphenyl)-amide of 5-(7-methylcarbamoylmethyl-5,6,7,8-tetrahydropyridoyl3,4-a|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

M. u

M H (c) H cheek (c)

Combination // 74-(1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-5,8-dihydro-6H-pyridoyZ3,4-

CH|Ipyrimidin-7-yl)-acetic acid (246 mg, 0.48 mmol), NATI (366 mg, 0.56 mmol), DIPEA (0.4 mL, 2.41 mmol) methylamine (201 μL, 0 .48 mmol, 2.0 M THF solution) and DMF (10 ml) are mixed in a sealed test tube at room temperature for 2 h. The reaction mixture is partitioned between DCM and 95% aqueous solution of GiSi. Then the organic layer is dried over anhydrous Mag5O", concentrated and the residue is purified using semi-preparative HPLC (C18; 10-100 965 ACN/H2O with the addition of 0.1 96 TFC). The combined fractions are diluted with a saturated aqueous solution of ManHsSoOz and extracted with EtOAc. Drying of the organic layer over Ma»5O»4, followed by filtration and concentration provides the desired compound. MS (ER) t/2 525.0 (Mat); "H NMR (400 MHz, mmeOb) b frequency/million 8.38 (5, 1 N), 8.33 (y, U-8.8 Hz, 1 N), 8.06 (5, 1 N) , 7.94 (a, 9-3.5 Hz, 1 H), 7.91 (5, 1 H), 7.57 (i, 9-8.0 Hz, 1 H), 7.44 (a , 2-7.8 Hz, 1 N), 7.40 (a, 90-2.3 Hz, 1 N), 7.10 (aa, 2-8.8, 2.3 Hz, 1 N), 6.74 (y, 90-3.5

Gu, 1 N), 3.75 (5.2 N), 3.00 (a, 9-5.3 Hz, 2 N), 2.90 - 2.96 (t, 2 N), 2.80 (5, Z H).

Example 42 42-А. Tert-butyl ether /4-oxo-3,5,7,8-tetrahydro-4H-pyrido|4,3-4|Ipyrimidine-6-carboxylic acid. (F) (e) Zh

year

M

6-Benzyl-5,6,7,8-tetrahydro-ZN-pyrido|4,3-4|pyrimidin-4-one (36.9 g, 153 mmol) and BOC anhydride (40.1 g, 184 mmol ) transferred to Meon (600 ml). The vessel is purged with argon and palladium on charcoal (10 95 wt/wt; wet) (5.0 g) is added. Then the contents are stirred in a hydrogen atmosphere (1 atm.) for 18 hours. Then the suspension is filtered through celite? and the solution is concentrated and the desired compound is obtained. MS (IER) t/2 252.0 (M--1). 42-B8. Tert-butyl ether of 4-chloro-7,8-dihydro-5H-pyrido|4,3-4|Ipyrimidine-b-carboxylic acid. (9 (e) p

With her

M

Triphenylphosphine (12.8 g, 48.7 mmol) is added to a solution of the compound of Example 42-A (6.08 g, 24.1 mmol), SiCl (7.0 ml, 72.3 mmol) and 1,2-dichloroethane (250 ml). Then the solution is heated at 70 "s.

After 2.5 hours the solution is concentrated in a vacuum to a volume equal to approximately 50 ml. Then the residue is purified by KFC (10-30 96 EOAc/heptane) and the desired compound is obtained. MS (ER) t/2 270.0 and 271.9 (M--1). 42-6. Tert-butyl ether of 4-(1H-indol-5-yloxy)-7,8-dihydro-5H-pyrido|4,3-4|pyrimidine-6-carboxylic acid. (in)

Rava;

M. M o Nn

Se tk

To a solution of the compound of example 42-B (0.250 g, 0.926 mmol), 5-hydroxyindole (0.160 g, 1.20 mmol) and

DBU (0.18 ml, 1.20 mmol) was added to SNZISM (5 ml). Then the mixture is heated at 50 °C for 3 hours.

Then the solvent is removed in vacuo and the residue is purified by KFC (10-50 96 EAs/heptane) to obtain the desired compound. MS (ER) t/2 367.1 (M.n1). 42-Ю0. Tert-butyl ether 4-P1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-7,8-dihydro-

BN-pyrido|4,3-4|Ipyrimidine-6-carboxylic acid. also ES av;

M u

M M o o nn

OK

Sodium hydride (0.030 g, 0.749 mmol, 60 95 in mineral oil) at 0 "C is added to a solution of the compound of example 42-C (0.183 g, 0.499 mmol) and THF (5 ml). After 15 minutes, 3-(trifluoromethyl )-phenyl isocyanate (0.14 ml, 0.0.998 mmol). After another 1.5 h, the contents of the flask are poured into buffer with pH 7 (50 ml) and extracted with DCM (2x25 ml). Then the combined organic layers dried (Mag250»4), filtered and concentrated.The crude residue was then purified using

KFC (20-50 90 EUAs/heptane). MS (ER) t/2 554.0 (M.n1). 42-BE. (3-Trifluoromethylphenyl)-amide of 5-(5,6,7,8-tetrahydropyrido|4,3-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

E.S

Ge) With vva;

M. 22 U

M

MN about M

TFC (1 ml) was added to a solution of the compound of example 42-O (0.136 g, 0.245 mmol) and DCM (5 ml). After 1 hour the solution is concentrated in a vacuum. The residue is transferred to Men and neutralized to pH 7 by adding MNAOH and then purified by semi-preparative HPLC (10-90 95 ACN/H2O with the addition of 0.1 95 MNAOH) and the desired compound is obtained. MS (IER) t/2 454.0 (M--1); "H NMR (400 MHz,

DMSO-dv) 6 ppm 10.38 (5, 1 N), 8.46 (5, 1 N), 8.27 (a, 9-91 Gu, 1 N), 8.12 (a, U-3.8 Hz, 1 N), 8.10 (5, 1 N), 7.97 (a, 9-81 Hz, 1 N), 7.65 (I, U-8.0 Hz, 1 H), 7.50 (a, U-7.3 Hz, 1 H), 7.46 (5, 1 H), 7.12 (da, 9-9.0, 2.4 Hz, 1 H) , 6.80 (a, 9-3.5 Hz, 1 N), 3.92 -4.09 (t, 2 N), 3.17 (I, U-5.7 Hz, 2 N), 2 .81 (I, 2-5.7 Hz, 2 N).

Example 43 43-А. (3-Trifluoromethylphenyl)-amide 5-(6-methyl-5,6,7,68-tetrahydropyrido|4,3-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

ES o) Z

Rava;

M. U

(3-Trifluoromethylphenyl)-amide 5-(5,6,7,8-tetrahydropyrido|4,3-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (example 42-E , 125 mg, 0.28 mmol), paraformaldehyde (16.6 mg, 0.55 mmol),

Mavni(Oas)z (117 mg, 0.55 mmol) and acetic acid (32 μL, 0.55 mmol) were dissolved in 1,2-DHE (7.5 mL) and heated at 60 °C for 4 h. Then the reaction mixture is partitioned between DCM and a saturated aqueous solution of MnSOO. The organic layer is then dried over anhydrous Ma»5O4 and concentrated in vacuo.

Meon/EOdAs 2:8) and get the desired compound. MS (IER) t/2 468.0 (M--1); "H NMR (400 MHz, MeOb) b frequency/million 8.41 (5, 1 N), 8.33 (a, U-8.8 Hz, 1 N), 8.06 (5, 1 N) , 7.93 (a, 9U-3.5 Hz, 1 N), 7.90 (a, U-9.3 Hz, 1 N), 7.57 (I, 9U-8.0 Hz, 1 N ), 7.44 (a, 90-7.6 Hz, 1 N), 7.41 (a, U-2.3 Hz, 1 N), 7.11 (da, U-9.0, 2, 4 Hz, 1 N), 6.74 (a, 9-3.8 Gu, 1 N), 3.74 (5.2 N), 2.96 - 3.04 (t, 2 N), 2, 87 - 2.94 (t, 2 H), 2.57 (5, C H).

The following compounds are obtained by a similar method. 43-8. (3-Trifluoromethylphenyl)-amide 5-(6-ethyl-5,6,7,8-tetrahydropyrido|4,3-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid

E,b kA) and more about

M. 22 u y o N

A mixture of (3-trifluoromethylphenyl)-amide 5-(5,6,7,8-tetrahydropyrido|4,3-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (example 42-E, 125 mg, 0 .28 mmol), acetaldehyde (31 μl, 0.55 mmol), mMavn(OdAc)z (117 mg, 0.55 mmol) and TEA (77 μl, 0.55 mmol) in 1,2-DHE were stirred at RT for 4 hours The mixture is then partitioned between DCM and a saturated aqueous solution

MansoOz. The organic layer is dried over anhydrous Mag25O4 and concentrated in vacuo. The crude residue was then purified by FCX (from Meon/EAc 1:9 to Meon/EuSO4 2:8) to give the desired compound (74 mg, 55,965). MS (IER) t/72 482.1 (M--1); "H NMR (400 MHz, MeOb) b frequency/million 8.57 (5, 1 N), 8.36 (y, 9-91 Hz, 1 N), 8.07 (5, 1 N), 7 - 7.48 (t, 2 H), 7.13 (aa, 9-9.0, 2.4 Hu, 1 H), 6.76 (a, 9-3.8 Hz, 1 H), 3, 43 - 3.54 (t, Z H), 3.26 (Bg. 5., Z H), 1.51 (I, U-7.3 Gu, Z H).

Example 44 44-А. Tert-butyl ether of 4-oxo-3,4,5,7-tetrahydropyrrolo|3,4-4|Ipyrimidine-b-carboxylic acid. (6) (6) pts

M o-4-

Formamidine hydrochloride (1.87 g, 25.5 mmol) was added to a solution of 1-tert-butyl ether of 3-ethyl ether of 4-oxopyrrolidine-1,3-dicarboxylic acid (2 g, 7.8 mmol) in EN (78 ml ), then Maogei (8.7 ml, 27.2 mmol). The reaction mixture is heated at 90 "C for 2 h. The reaction mixture is then evaporated and a saturated solution of ammonium chloride (20 ml) is added, followed by DCM (80 ml). The layers are separated and the aqueous layer is further extracted with DCM (50 ml x 3). The organics are combined, dried and evaporated to give the crude product.

Meon). MS (IER) t/2 238.2 (M.H1). 44-V. Tert-butyl ether of 4-(1H-indol-5-yloxy)-5,7-dihydropyrrolo|3,4-4|Ipyrimidine-b-carboxylic acid. (6)

SH If;

M. 2 M

N

M

)-o x

To a solution of tert-butyl ether of 4-oxo-3,4,5,7-tetrahydropyrrolo|3,4-4|Ipyrimidine-b-carboxylic acid (74 mg, 0.31 mmol) in acetonitrile (3 ml), add BOP (179 mg, 0.405 mmol), then DBU (0.094 ml, 0.624 mmol). In 20 minutes. add 5-hydroxyindole (83 mg, 0.624 mmol). The reaction mixture is stirred at RT for 3 h. The reaction mixture is evaporated and the crude product is purified by HPLC on silica gel (elution in gradient mode from 100 95 heptane to 6O 95 heptane/40 95 ethyl acetate) to obtain the desired compound. MS (ER) t/2 353.1 (M.n1).

The following compounds are obtained by a similar method. 44-S. Tert-butyl ether of 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5,7-dihydropyrrolo|3,4-4|pyrimidine-b-carboxylic acid.

IS

M (c) сх Со-

M. 2 M

N

M

- about x

MS (ER) t/2 385.9 (M--1). 44-00. Tert-butyl ether of 4-(4-fluoro-1H-indol-5-yloxy)-5,7-dihydropyrrolo|3,4-4|pyrimidine-6-carboxylic acid.

And more) skh So

M. and M

N

M

- about x

The method is carried out as described above (example 44-B), using RUVOR instead of VOR.

MS (ER) t/2 369.1 (M-1). 44-E. Tert-butyl ether of 4-(2-methyl-1H-indol-5-yloxy)-5,7-dihydropyrrolo|3,4-4|Ipyrimidine-6-carboxylic acid.

He) g X 25-

M M

N

M

- about x

The method is carried out as described above (example 44-B) using RUVOR instead of VOR.

MS (ER) t/2 365.1 (M-1).

Example 45 45-А. Tert-butyl ether of 4-(1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-5,7- dihydropyrrolo|3,4-4|Ipyrimidine-b-carboxylic acid.

E.S

M. o i vav;

MO M

M o )-o h

To a solution of 4-(1H-indol-5-yloxy)-5,7-dihydropyrrolo|3,4-4|pyrimidine-6-carboxylic acid tert-butyl ether (3.59 g, 10.2 mmol) in THF ( 100 ml) at 0 "С add Mann (0.611 g, 15.3 mmol).

In 10 minutes. 1-isocyanato-3-trifluoromethylbenzene (2.93 mL, 20.4 mmol) was added and the reaction mixture was allowed to warm to room temperature. After 2.5 hours add a saturated solution of MNASI in water (50 ml). The mixture is extracted with EOAc (x3) and the combined organic extracts are dried and evaporated to give crude tert-butyl ether 4-(1-(3-trifluoromethylphenylcarbamoyl)-1H-

Indole-5-yloxy|-5,7-dihydropyrroloY3,4-4|Ipyrimidine-b6-carboxylic acid. MS (IER) t/2 540.9 (M.--1). 45-8. (3-Trifluoromethylphenyl)-amide of 5-(6,7-dihydro-5H-pyrrolo|3,4-4|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid.

Che ES vav;

Mo 2 M

M Hmm

N (6) N

To a solution of tert-butyl ether of 4-(11-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-5,7-dihydropyrrolo|3,4-4|Ipyrimidine-b6-carboxylic acid in DCM (20 ml) TFA (20 mL, 260 mmol) was added at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for an additional 1 h. 20 mL). The organic layer is separated and the aqueous layer is further extracted with EAs (2x). The combined organics are dried and evaporated. The crude residue is purified by KFC (eluting with a mixture of DXM/Meon/lmMmnNaOOnH (from 100:0:0 to 93:6:1)) and obtain (3-trifluoromethyl phenyl)-amide of 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid. MS (ER) t/2 440.9 (M--1); "H NMR (400 MHz, mMeor) 5 ppm 8.55 (5, 1 H), 8.33 (a, 9U-8 .84 Hz, 1 H), 8.06 (g. 5., 1 H), 7.89 (a, 9U-8.34 Hz, 1 H), 7.94 (y, 9-3.54 Hz , 1 N), 7.57 (I, 9U-7.96 Hz, 1

H), 7.41 - 7.46 (t, 2 H), 7.13 (da, 9U-9.09, 2.27 Hz, 1 H), 6.74 (y, 9-3.03 Hz , 1 H), 4.26 (y, 9U-12.13 Hz, 4 H).

The following compounds are obtained by a similar method.

SHCI Structure/chemical name "H NMR (400 MHz) Me Ai tu

And Es

M (c); With E

Ty -- x (meOb) 5 parts/million 8.55 (5.1 N),

M. Zh M 8.08 (ad, 9U-6.32, 2.78 Hz, 1 H), 7.91

M (a, U-9.03, 3.44 Hz, 1 H), 7.49 (y, 45-20 M M 3-8.84 Hz, 1 H), 7.37 (, U-9, 60 Hz, 1,490.9

H o nH H), 7.08 (ad, U-8.84, 7.33 Hz, 1 H), (4-fluoro-3-trifluoromethyl-phenyl)-amide | 6.50 (5, 1 H), 4.48 (rg. 5., 2 H) 4.37 6,7-dihydro-5H-pyrrolo!|3,4-a|pyrimidine- | (bg. 5., 2 H) 2.60 (a, 9U-1.01 Hz, Z H). 4-yloxy)-4-fluoro-2-methylindole-1-carboxylic acid

E more) with E and E-with x (meOb) 5 parts/million 8.52 (5, 1 N), c r M 8.32 (a, 9U-9.09 Hz, 1 N), 8, 04 (aa, 3-6.19, 2.15 Hz, 1 H), 7.91 (a, 9U-3.54 45-20 M rya Gu, 2 H), 7.42 (a, 9-2 ,02 Hz, 1 N), 458.9

Nn o nn 7.34 (I, 9-9.60 Hz, 1 H), 7.11 (aa, (4-fluoro-3-trifluoromethyl-phenyl)-amide |9U-8.97, 2.15 Hz . .84 Gu, 4 N). 4-yloxy)-indole-1-carboxylic acid

IS

IS

Mao Zedong

Ti Z (meOb) 5 parts/million 8.57 (5.1 N),

M. In 8.09 (5, 1 N), 7.87 (a, 9-8.08 Hz, 1 N),

Y 7.59 (I, 9-7.96 Hz, 1 H), 7.45 - 7.51 45E M o y (t, 2 H), 7.10 (а9.9-8.72.7, 45 Hz, 1 7729 . . Н), 6.52 (5. 1 Н), 4.53 (Bg. zn) ) dihydro-5H-pyrrolo|3,4-4|pyrimidine-4-' 7 '' I yloxy)-4-fluoro-2-methylindole-1- carboxylic acid

E.b fi ts in M (DMSO-sv) b freq./million 8.56 (5.1 N),

E 18.27 (a, U-8.84 Hz, 1 H), 8.10 (a,

AB-E M Hm 93.54 Gu, 1 H), 7.88 - 7.93 (t, 2 H), 4589

H o nH 7.49 (4.9-2.02 Hz, 1 H), 7.41 - 7.45 '(Z-fluoro-5-trifluoromethyl-phenyl)-amide | (t, 1 H), 7.14 - 7.18 (t, 1 H), 6.81 5-(6,7-dihydro-5H-pyrrolo|3,4- (reg. 5., 1 H) , 4.08 (5.4 H). ! (DMSO-dv) 6 ppm 8.56 (5.1 N),

M. mi C 8.24 (4, 4-9.09 Hz, 1 N), 8.09 (4, m r Z Tu 3.54 Hz, 1 N), 7.89 - 8.01 (t, 1 H), 45-44 N o nn E 7.66 - 7.73 (t, 1 H), 7.45 - 7.58 (t, 458.9 (2-fluoro-3-trifluoromethyl-phenyl)- amide E do c Pd Ne t, M, 5-(6,7-dihydro-5H-pyrrolo|3,4- ziz8og a tbo, d9|Ipyrimidin-4-yloxy)-indol-1-' c, and carboxylic acid acids also Rab t s If; (meOb) 5 ppm 8.53 (5.1 N),

Mo. 22 M 8.30 (a, U-8.84 Hz, 1 N), 8.15 - 8.20 r (t, 1 N), 7.88 - 7.92 (t, 1 N), 7, 58 45-H ich o H E (aaa, 9U-6.13, 3.98, 2.27 Hz, 1 H), 7.39 458.9 01-7,A6 (t, 2 H), 7, 12 (da, 2-9.09, (g-fluoro-o-trifluoromethyl-phenyl)-amide 2.02 Hz, 1 H), 6.74 (y, 9-3.79 Hz, 1 5-(6 ,7-dihydro-5H-pyrrolo|3,4- H), 4,19 (a, 9-9,35 Hz, 4 H). d9|Ipyrimidin-4-yloxy)-indole-1- carboxylic acid

Che Rab t s If; (meOb) 5 parts/million 8.53 (5.1 N),

E. 22 M 8.30 (a, U-8.84 Hz, 1 N), 8.15 - 8.20 rya (t, 1 N), 7.88 - 7.92 (t, 1 N), 7, 58 45-I M o ns (as, 9-6.13, 3.98,2.27 Hz, 1 H), 7.39... 475.9 001-746 (t, 2 H), 7, 12 (yes, Y-9.09, (g-chloro-o-trifluoromethyl-phenyl)-amide 2.02 Hz, 1 H), 6.74 (y, 9-3.79 Hz, 1 5-(6 ,7-dihydro-5H-pyrrolo|3,4- H), 4,19 (a, 9-9,35 Hz, 4 H). d9|Ipyrimidin-4-yloxy)-indole-1- carboxylic acid

M. ,0 as SI t se If; (meob) 5 parts/million 8.53 (5.1 N),

M. 22 M 8.30 (a, U-8.84 Hz, 1 N), 8.15 - 8.20 u (t, 1 N), 7.88 - 7.92 (t, 1 N), 7.58 45th M o y (as, 9-6.13, 3.98,2.27 Hz, 1 N), 7.391. 475.9 001-746 (t, 2 H), 7.12 (yes, Y-9.09, (4-chloro-3-trifluoromethyl-phenyl)-amide 2.02 Hz, 1 H), 6.74 (y, 9-3.79 Hz, 1 5-(6,7-dihydro-5H-pyrrolo|3,4- H), 4.19 (a, 9-9.35 Hz, 4 H). d9| Ipyrimidin-4-yloxy)-indole-1-carboxylic acid; he X (meob) b frequency/million 8.52 (5, 1 H), these r M 8.07 (5, 1 H), 7.87 (9, U-7.83 Hz, 1 H), 7.69 (a, U-8.59 Hz, 1 H), 7.59 (i, 45-K M zh ChueT, 71 Hz, 1 H), 7.46 (4.9-8.08 Hz, 1 0 453.9

H o n H), 7.30 (4.9-2.02 Hz, 1 H), 7.02 (a, (3-trifluoromethylphenyl)-amide 5-(6.7- 78.84, 2.27 Hz, 1 N), 6.44 (5.1 N), dihydro-5H-pyrrolo|3,4-a|pyrimidine-4- | 4.18 (bg. 5., 4 N), 2.61 ( 5, C H).yloxy)-2-methylindole-1-carboxylic acid of ShFquislotia7///11111111Ї111111111111111111111111111111111111Ї11

M., O | (meOb) 5 parts/million 8.56 (5.1 N), and t If; m" 8.33 (a, 9U-8.84 Hz, 1 N), 7.93 (a,

М. 8.84, 2.27 453.0

M o i Hz, 1 N), 6.75 (a, 9U-3.54 Hz, 1 N),

H 4.30 (a, 9-12.38 Hz, 4 H), 2.31 (5, C (5-methyl-1-phenyl-1 H-pyrazol-4-yl)- H). Amide 5-(6,7-dihydro-5H-pyrroloi|3,4-d9|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid pe o X (DMSO-α) 6 ppm 9.67 ( 5, 1 N), va M 8.56 (5, 1 N), 8.24 (a, U-8.84 Hz, 1 N), 8.09 (a, 9U-3.79 Hz, 1 N ), 7.47 (a,

M Hm y-2.53 Hz, 1 H), 7.17 (a, 9-7.58 Hz, 1 45-M H o nH o H), 7.12 (da, 9-5.81, 3 ,03 Hz, 1 H), 4421 (2,2-dimethyl-2,3-dihydrobenzofuran-7.10 (5, 1), b,b4 (635771 4,1), 7-yl)-amide 5-(6, 7-Dihydro-5H-pyrrolo|3,4- 6.75 (9, 93.79 Hz, 1 H), 4.09 (y, aIpyrimidin-4-yloxy)-indole-1-rte, 35 g, 2 H) , ov l12 (t, 2 N), and 3.08 (5, 2 N), 1.44 (5.6 N) of carboxylic acid.

What;

M "C (me) 5 parts/million 8.53 (5.1 N),

Tj 8.14 (a, 9U-9.09 Hz, 1 H), 8.06 (5, 1 H), va U 7.95 (a, 9U-3.79 Hz, 1 H), 7.90 (а, у-7.58 Hz, 1 H), 7.58 (I, У-8.08 Hz, 1 45-М Мо и Н), 7.45 (а, У-7.58 Hz, 1 H), 7.21 (aa, 0098 (3-trifluoromethylphenyl)-amide 6,7- p raz v, beans E va dihydro-5H-pyrroloi|3,4-4|pyrimidine-4- pe? p "33 6, ), 421 (6951, yloxy)-4-fluoroindole-1-carboxylic acid B, )

IS

M. 0 and B MH (DMSO-dv) 6 parts per million 8.57 (5.1 N),

M. 2 M y, 8.13 (a, 9U-3.79 Hz, 1 H), 8.08 (y, p E 3-8.84 Hz, 1 H), 7.95 (her, U- 7.58 Hz, 1 45-0 M o her E E NU, 7.71 (1. 9-7.33 Hz, 1 H), 7.49 (i, 476.1

H 3-8.08 Hz, 1 H), 7.31 (a, 9U-7.83 Hz, 1 (2-fluoro-3-trifluoromethyl-phenyl)-amide | H), 6.93 (a, 9 -3.54 Hz, 1 H), 4.23 (5.2 6,7-dihydro-5H-pyrrolo|3,4-a|pyrimidine- | H), 4.10 - 4.13 (t, 2 N). 4-yloxy)-4-fluoroindole-1-carboxylic acid

Example 46 46-А. (3-Methoxy-5 trifluoromethylphenyl)-amide of 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

Che ES vav;

M. M. OMe

M Hmm

N o nn

To a solution of 4-(1H-indol-5-yloxy)-5,7-dihydropyrrolo|3,4-4|pyrimidine-6-carboxylic acid tert-butyl ether (158 mg, 0.44 mmol) in DMF (4 ml ) in one portion add KDI (145 mg, 0.89 mmol), then TEA (0.537 ml, 2.7 mmol). After three hours at RT, 3-methoxy-5-trifluoromethylphenylamine (514 mg, 2.7 mmol) and DMAP (5.5 mg, 0.04 mmol) were added, and the reaction mixture was stirred for 40 h. Add ethyl acetate (2 ml), then add 1 n. NSI solution (3 ml).

Organic substances are extracted with EtOAc (x3) and concentrated. The crude mixture is dissolved in SiO2 (10 mL) and cooled to 0 °C and TFA (10 mL, 130 mmol) is added. The reaction mixture is allowed to warm to RT over 2 h. The reaction mixture is evaporated, redissolved in

KODAs and add a few drops of MNAON to the free base of the amine. The solvent is removed and the residue is purified by KFC (DHM/Meon/lmMnAsn (from 100:0:0 to 93:6:1)) to obtain (3-methoxy-5-trifluoromethylphenyl)-amide 5-(6,7-dihydro- 5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid. MS (ER) t/2 471.0 (M--1); "H NMR (400 MHz, Meob) 5 ppm 8.50 - 8.56 (t, 1 H), 7.93 (y, 9-3.54 Hz, 1 H), 7.59 (y , 9U-19.71 Hz, 2 H), 7.42 (y, 9-2.27 Gu, 1 H), 7.12 (yes, 9-8.97, 2.40 Hz, 1 H), 6.96 (5.1 N), 6.73 (9.9-3.79 Hz, 1 N), 6.52 (5.1 N), 4.19 (a, 9U-8.34 Hz, 4 H), 3.76 (5, C H).

The following compounds are obtained by a similar method. 46-88. (5-Trifluoromethyl-2H-pyrazol-3-yl)-amide 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

SE ee o x Z ! Be

Mo. 22 M in M

Mr. N

N o nn

MS (IER) t/2 431.9 (M-4T1) "H NMR (400 MHz, meob) b frequency/million 8.44 (5.1 H), 8.32 (y, 9U-9.09 Gu, 1

NO, 7.78 (9, 9-3.54 Hz, 1 H), 7.33 (5, 1 H), 7.05 (a, 9-7.33 Gu, 1 H), 6.66 ( a, 9U-3.54 Hz, 1 H), 6.43 (bBg. 5., 1

H), 5.35 (5, 1 H), 4.12 (y, 9-13.14 Hz, 4 H). 46-60. 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (5-tert-butyl-2H-pyrazol-3-yl)-amide.

MO zh i s

M. 2 M | M

M Hm N

N o nn

MS (IR) t/2 418.1 (M-nt) "H NMR (400 MHz, meob) b freq./million 8.51 (5, 1 H), 8.31 (a, 9U-9.09 Hz, 1

NO, 7.87 (9, 9U-3.54 Hz, 1 H), 7.40 (y, 9-2.53 Hz, 1 H), 7.10 (ad, 9U-8.97, 2, 40 Hz, 1 N), 6.69 (a, 9U-3.54 Hz, 1

H), 6.38 (5, 1 H), 4.17 (a, 9-7.07 Hz, 4 H), 1.36 (5, 9 H).

Example 47 47-А. Ethyl ether of (5)-2-benzylaminopropionic acid. in

Ethylalanine hydrochloride (5.5 g, 36.8 mmol), benzaldehyde (7.9 mL, 77.8 mmol), TEA (10.8 mL, 77.8 mmol), and Mavn(Oas)z (16.5 g, 77.8 mmol) is transferred to 1,2-DHE (200 ml) and stirred at RT for 4 h. Then the reaction mixture is partitioned between DCM and a saturated aqueous solution of ManHsSoOz. The organic layer is separated, dried over anhydrous Mag5O4 and concentrated in vacuo. The crude residue is used without further purification. MS (ER) t/ 208.2 (M--1). 47-V. (x)-4-I(benzyl-(1-ethoxycarbonylethyl)-amino|-butyric acid methyl ester

2-Benzylaminopropionic acid ethyl ether (1.4 g, 6.7 mmol), methyl oxobutanoate (1.7 g,

13.5 mmol), TEA (1.9 mL, 13.5 mmol) and Mavn(Cas)z (2.9 g, 13.5 mmol) were transferred to 1,2-DHE (35 mL) and stirred at RT for 4 hours The reaction mixture is partitioned between DCM and a saturated aqueous solution of MansSoz. The organic layer is separated, dried over anhydrous Ma»5O» and concentrated in vacuo. The crude residue is used without further purification. MS (ER) t/2 308.3 (M--1). 47-S. Methyl ether of (5)-1-benzyl-2-methyl-3-oxopiperidine-4-carboxylic acid. (c) yes

M iso

A mixture of 4-|benzyl-(1-ethoxycarbonylethyl)-amino|-butyric acid methyl ester (1.5 g, 4.9 mmol), potassium tert-butoxide (906 mg, 8.9 mmol) and toluene (100 mL) stir at CT for 3 hours. Then the mixture is partitioned between DCM and a saturated aqueous solution of MNASI. The organic layer is separated, dried over anhydrous Ma»5O:4 and concentrated. The crude residue is used without further purification. MS (IER) t/ 262.2 (M.-1). 47-0О. (3)-7-Benzyl-8-methyl-5,6,7,8-tetrahydro-ZN-pyrido|3,4-4|pyrimidin-4-one. (6)

SS n-

M M

A mixture of 1-benzyl-2-methyl-3-oxopiperidine-4-carboxylic acid methyl ester (1.0 g, 3.9 mmol), formamidine hydrochloride (930 mg, 11.6 mmol) and EUN (6 ml) was treated with Maoyi's solution (5.5 ml, 13.57 mmol, 21 95 wt./wt. in ЕН) and the reaction mixture is stirred at 90 "C for 2 h. The pH value is adjusted to 6 and then the reaction mixture is concentrated in vacuo. The residue is purified using semi-preparative HPLC (C18; 10-100 95 ACN/H2gO with the addition of 0.195 MNAOH) and obtain the desired compound. MS (ER) t/2 256.0 (M.n1). 47-E. (g)-8-Methyl- tert-butyl ether /4-oxo-4,5,6,8-tetrahydro-ZN-pyrido|3,4-4|pyrimidine-7-carboxylic acid. (c) m

FU MAO wa tk 7-Benzyl-8-methyl-5,6,7,8-tetrahydro-ZN-pyrido|Z,4-4|pyrimidin-4-one (359 mg, 1.41 mmol) and BOC-anhydride (368 mg, 1.69 mmol) is taken up in Meon (20 mL) and THF (20 mL). To this solution, add Ra/C (75 mg, 20 Fo w/w) and the mixture is stirred in a hydrogen atmosphere (1 atm.) for 3 h.

The mixture is filtered through a layer of celite and the filtrate is concentrated to obtain the desired compound, which is used without additional purification. MS (IER) t/2 266.1 (М--Н). 47-E. Tert-butyl ether of (g)-4-chloro-8-methyl-5,8-dihydro-6H-pyridoyl3,4-4|pyrimidine-7-carboxylic acid.

SI

WITH

I M (F) m ve tk

A combination of 4-oxo-4,5,6,8-tetrahydro-3,4-4|pyrimidine-7-carboxylic acid 8-methyl-tert-butyl ether (374 mg, 1.41 mmol), triphenylphosphine (739 mg, 2.82 mmol) and carbon tetrachloride (409 μl, 4.23 mmol) and 1,2-DHE (10 ml) are heated at 70 °C for 6 h. The solution is then concentrated in vacuo and the residue is purified by KFC ( 5-60 96 EOAc/heptane). MS (IER) t/2 284.2 (M.H). 47-65. Tert-butyl ether (g)-4-(1H-indol-5-yloxy)-8 -methyl-5,8-dihydro-6H-pyrido|3,4-4|pyrimidine-7-carboxylic acid.

(c) wav;

M. M

N

M. a

To a solution of tert-butyl ether of 4-chloro-8-methyl-5,8-dihydro-6H-pyrido|3,4-4|pyrimidine-7-carboxylic acid (228 mg, 0.80 mmol), 5-hydroxyindole ( 139 mg, 1.05 mmol) and MesM (5 mL) add DBU (0.15 mL, 1.05 mmol). The resulting mixture is heated at 807"C for 4 hours. Then the reaction mixture is concentrated in a vacuum and the residue is purified using KFC (5-60 95

EtOAc/heptane). MS (ER) t/2 381.1 (M.N). 47-N. Tert-butyl ether (x)-8-methyl-4-(1-(3-trifluoromethylphenyl-carbamoyl)-1H-indol-5-yloxy|-5,8-dihydro-6H-pyridoyl3,4-a|pyrimidine- 7-carboxylic acid.

Mo U

M

M o nn a

A solution of 4-(1H-indol-5-yloxy)-8-methyl-5,8-dihydro-6H-pyridoyl3,4-4|pyrimidine-7-carboxylic acid tert-butyl ether (224 mg, 0.50 mmol) and THF (8 mL) is cooled to 0 °C. Man (35 mg, 0.88 mmol, 60 95 in mineral oil) is added, then 3-trifluoromethyl isocyanate (164 µL, 1.18 mmol) and the mixture is allowed to warm to room temperature. After the end of the reaction according to LCMS, the mixture is partitioned between DCM and a buffer solution with pH 7. The organic layer is separated, dried over anhydrous Mag250O54 and concentrated. The crude residue is purified using KFC (5-60 95

EtOAc/heptane) and obtain the desired compound. MS (IER) t/2 568.1 (M--1). 47-I. (3-Trifluoromethylphenyl)-amide (5)-5-(8-methyl-5,6,7,8-tetrahydro-pyridoyl3,4-d|pyrimidin-4-yloxy)-indole-1-carboxylic acid. what)

Ge) With yours;

M. 22 U

M

M o nn

N

Solution of tert-butyl ether 8-methyl-4-|1-(3-trifluoromethylphenyl-carbamoyl)-1H-indol-5-yloxy|- 5,8-dihydro-6H-pyridoi|3,4-4|Ipyrimidine- 7-carboxylic acid (217 mg, 0.38 mmol), DCM (5 mL) and TFA (5 mL) were stirred at RT for 2 h. Then the solution is concentrated in a vacuum and the residue is purified by means of semi-preparative HPLC (C18; 100-100 95 ACN/H2gO with the addition of 0.195 MNAOH) and the desired compound is obtained. MS (ER) t/2 468.1 (M--1); "H NMR (400 MHz, DMSO-av) b freq./million 10.39 (5, 1 N), 8.51 (5, 1 N), 8.28 (y, 9-91 Hz, 1 N) , 8.06 - 8.15 (t, 2 H), 7.97 (a, 9U-8.6 Hu, 1 H), 7.65 (I, U-8.0 Hu, 1 H), 7 .43 - 7.53 (t, 2 N), 7.13 (a9, U-9.0, 2.4 Hz, 1 N), 6.60 (y, 9U-3.5 Gu, 1 N) , 4.19 (9, 9U-6.6 Gu, 1 H), 3.34 - 3.42 (t, 1 H), 3.08 - 3.20 (t, 1 H), 2.88 ( I, 9-5.7 Hz, 2 H), 1.49 (a, 9-71 Hz, C H).

Example 48 48-А. 4-P1-(3-trifluoromethoxyphenylcarbamoyl)-1H-indol-5-yloxy|-5,8-dihydro-bH-pyridoyl3,4-4|pyrimidine-7-carboxylic acid tert-butyl ether.

Fe) o) Z vav;

M. U.

M

M o nn oho

A solution of 4-(1H-indol-5-yloxy)-5,8-dihydro-6H-pyridoyl3,4-4|pyrimidine-7-carboxylic acid tert-butyl ether (example 31-C, 300 mg, 0.82 mmol ), KDI (265 mg, 1.64 mmol), TEA (342 μL, 2.46 mmol), and DCM (5 mL) were stirred at RT for 1 h, then 3-trifluoromethoxyaniline (435 mg, 2.46 mmol) was added ). Another 24 hours later. the reaction mixture is concentrated in vacuo and purified by KFC (5-90 96 EOAc/heptane) and the desired compound is obtained. MS (IER) t/2 564.1 (M.n1). 48-8. (3-Trifluoromethoxyphenyl)-amide of 5-(5,6,7,8-tetrahydropyrido|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

E.co

Ge) With yours;

M. 22 U

M

M o nn

N

A solution of tert-butyl ether of 4-P1-(3-trifluoromethoxyphenylcarbamoyl)-1H-indol-5-yloxy|-5,8-dihydro-6bH-pyrido/3,4-4|pyrimidine-7-carboxylic acid (212 mg, 0.37 mmol), DCM (5 ml) and TFC (5 ml) are stirred at RT for 2 h. Then the solution is concentrated in a vacuum and purified by means of semi-preparative HPLC (C18; 10-100 965 ACN/HgO with the addition of 0.1 95 MNAOH) and the desired compound is obtained. MS (IER) t/ 470.0 (M--1); "H NMR (400 MHz, Meob) 5 ppm 8.41 (5, 1 H), 8.33 (y, 9-91 Gu, 1 H), 7.93 (9, 2-3.8 Hz, 1 H), 7.74 (5, 1 H), 7.62 (aa, U-8.2, 1.1 Gu, 1 H), 7.46 (I, 90-8.2 Hz, 1 N), 7.40 (a, 9-2.3 Hz, 1 N), 7.00 - 7.15 (t, 2 N), 6.73 (ad, 9-3.8 Hz, 1 N ), 4.05 (5, 2 N), 3.31 - 3.29 (M, observed, 2 N), 2.96 (I, U-5.7 Hz, 2 N).

Example 49 49-А. Tert-butyl ether 4-(1-15-(2-(tert-butyldimethylsilanyloxy)-1,1-dimethylethyl|-2H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy)-5,8- dihydro-6H-pyrido|3,4-4Y|pyrimidine-7-carboxylic acid.

Open 5

Mo zh i s

M. mo l, kh

M o nn oo

A solution of 4-(1H-indol-5-yloxy)-5,8-dihydro-6H-pyridoyl3,4-4|pyrimidine-7-carboxylic acid tert-butyl ether (example 31-C, 200 mg, 0.55 mmol ), KDI (177 mg, 1.10 mmol), TEA (0.23 mL, 1.64 mmol), and DMF (5 mL) were stirred at RT for 1 h, then 5-(2-(tert-butyldimethylsilanilox) was added )-1,1-dimethylethyl|-2H-pyrazole-3-ylamine (441 mg, 1.4 mmol) and 4-pyrrolidinepyridine (4 mg, 27 μmol). After 24 h, the solution was concentrated in vacuo and the residue was purified by KFC (5-90 95 EIOAc/heptane) and get the desired compound. MS (IER) m/: 662.3 (M-1). 49-8. I5-(2-Hydroxy-1,1-dimethylethyl)-2H -pyrazol-3-yl|-amide 5-(5,6,7,8-tetrahydropyridoyl3,4-a|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

he

M (in)

Sg a

M. Mo h-m y

M o nn

N

Tert-butyl ether solution 4-(1-5-(2-(tert-butyldimethylsilanyloxy)-1,1-dimethylethyl|-2H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy)-5,8 -dihydro-6H-pyrido/3,4-4|pyrimidine-7-carboxylic acid (252 mg, 0.38 mmol), DCM (2 mL) and TFA (2 mL) were stirred at RT for 2 h. Then the solution is concentrated in a vacuum and the residue is purified using semi-preparative HPLC (C18; 10-100 95

ACN/HgO with the addition of 0.1 95 MNAOH) and obtain the desired compound. MS (ER) t/2 448.1 (MaА1); "N

NMR (400 MHz, Meob) 5 ppm 1.33 (5.6 N), 2.92 (Her, 9-5.43 Hz, 2 N), 3.25 (I, 9-5.94 Hz, 2 N), 3.30 (5.2

H), 3.57 (5, 2 H), 4.02 (5.2 H), 6.40 (in, 1 H), 6.70 (y, 9-3.54 Hz, 1 H), 7.07 (yes, 9-8.97, 2.15 Hz, 1 H), 7.38 (5, 1 H), 7.88 (y, 9U-3.79 Hz, 1 H), 8, 31 (a, 9-9.09 Hu, 1 H), 8.39 (5, 1 H).

Example 50 50-А. Ethyl ether of 4-(1-phenylethylamino)-pentanoic acid. (in)

H

Racemic 1-phenylethylamine (10 g, 83 mmol), ethyl levulenate (11.76 mL, 83 mmol), Mavn(oOds)z (35 g, 165 mmol), and 1,2-DHE (200 mL) were stirred at RT for 4 hours The mixture is then partitioned between DCM and a saturated aqueous solution of Mansaoz. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude residue is used without further purification. MS (ER) t/2 250.2 (M.n1). 50-V. Ethyl ether of 4-(ethoxycarbonylmethyl-(1-phenylethyl)-amino|-pentanoic acid. (6) in (c) IF

A combination of 4-(1-phenylethylamino)-pentanoic acid ethyl ether (20.5 g, 82 mmol), ethyl glyoxylate (33 ml, 165 mmol, 50 95 solution in toluene), Mavn(OAc)»z (34.9 g, 165 mmol) and 1,2-

DHE (200 ml) is stirred at CT for 4 hours. Then the mixture is partitioned between DCM and a saturated aqueous solution of MansSoz. The organic layer is separated, dried over anhydrous Ma»5O» and concentrated in vacuo. The crude residue is used without further purification. MS (ER) t/2 336.4 (M--1). 50-S. 2-methyl-5-oxo-1-(1-phenylethyl)-piperidine-4-carboxylic acid ethyl ester. (in)

M (in)

A mixture of 4-(ethoxycarbonylmethyl-(1-phenylethyl)-amino|-pentanoic acid ethyl ether (13 g, 39 mmol), KiOVy (10.9 g, 97 mmol) and toluene (300 ml) was stirred at RT for 3 h. The mixture was then partitioned between DCM and a saturated aqueous solution of MNACI. The organic layer was separated, dried over anhydrous Mag50" and concentrated in vacuo. The crude residue was purified by KFC (5-30 96 EAs/heptane) to give the desired compound. MS (ER) t/2 290.3 (M.n1). 50-0. 6-Methyl-7-(1-phenylethyl)-5,6,7,8-tetrahydro-ZN-pyridoyi3,4-4|pyrimidine-4- he

ov -

M M

A combination of 2-methyl-5-oxo-1-(1-phenylethyl)-piperidine-4-carboxylic acid ethyl ether (7.4 g, 25.6 mmol), formamidine acetate (7.98 g, 77 mmol) and EN ( 60 ml) is treated with Maogei's solution (36.7 ml, 90 mmol, 21 95 wt./wt. solution in EN) and then heated at 90 "C for 4 h.

Then the pH value is adjusted to 6 and the mixture is concentrated in a vacuum. The residue is partitioned between DCM and a saturated aqueous solution of MNASI. The organic layer is separated, dried over anhydrous

Mag5O: and concentrate in a vacuum. The crude residue is purified using KFC (1-10 95

MeonH/DHM) and get the desired compound. MS (IER) t/2 270.1 (M-H1). 50-E. (3)-6-Methyl-tert-butyl ether of 4-oxo-4,5,6,8-tetrahydro-ZN-pyridoyi3,4-4|pyrimidine-7-carboxylic acid (6) 8; p- yy (6)

To a mixture of b-methyl-7-(1-phenylethyl)-5,6,7,8-tetrahydro-ZN-pyrido|3,4-Yad|Ipyrimidin-4-one (6.8 g, 25.2 mmol) , ammonium formate (7.96 g, 126 mmol), BOC anhydride (8.27 g, 37.9 mmol), MeOnH (250 mL), and

THF (167 ml) is added 10 95 Ra/C (1.36 g, 20 95 w/w) and the reaction mixture is refluxed for 3 h. Then the mixture is filtered through a layer of Celite? and the filtrate is concentrated. The residue is purified using KFC (1-10 96 Meon/DdhM) and the desired compound is obtained. MS (IER) t/2 266.1 (М--Н). 50-R. Tert-butyl ether (5z)-4-chloro-6-methyl-5,8-dihydro-6H-pyridoyl3,4-4|pyrimidine-7-carboxylic acid.

SI ov.

OM - in m rn

A solution of (x)-6-methyl-tert-butyl 4-oxo-4,5,6,8-tetrahydro-ZH-pyridoI3,4-4|pyrimidine-7-carboxylic acid (7.5 g, 28.3 mmol), triphenylphosphine (14.8 g, 56.5 mmol) and carbon tetrachloride (8.2 ml, 85 mmol) in 1,2-DCHE (100 ml) is heated at 80 "C for 6 h. Then the solution is concentrated in vacuum and the residue is purified using KFC (5-60 90 E(OAc/heptane) and the desired compound is obtained. MS (IR) t/2 284.1 (M--H). 50-06. tert-butyl ether (5t )-4-(1H-indol-5-yloxy)-6-methyl-5,8-dihydro-6H-pyrido3,4-4|pyrimidine-7-carboxylic acid. (c)

Rava;

M. M

N

Ma I

A solution of tert-butyl ether //(5)-4-chloro-6-methyl-5,8-dihydro-6H-pyrido|3,4-4|pyrimidine-7-carboxylic acid (220 mg, 0.77 mmol ), 5-hydroxyindole (155 mg, 1.16 mmol) and MesmM (10 mL) were treated with DBU (0.2 mL, 1.16 mmol) and heated at 80 "C for 4 h. The volume was reduced to vacuum and the residue was purified by KFC (5-90 906 EtOAc/heptane) to give the desired compound MS (IR) t/2 381.3 (M--H).

The following compounds are obtained by a similar method. 50-N. Tert-butyl ether (zt)-4-(4-fluoro-1H-indol-5-yloxy)-6-methyl-5,8-dihydro-6H-pyridoyl3,4-

α|pyrimidine-7-carboxylic acid.

And also) --sh is SO

M. M

N

M. a

MS (ER) t/2 399.1 (M-A-H).

Example 51

B51-A. Tert-butyl ether ("(g)-4-11-(5-tert-butyl-2H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy|-6-methyl-5,8-dihydro- 6H-pyridoyi3,4-4|Ipyrimidine-7-carboxylic acid.

Mao x (and MN

M. M. WE already M

M o nn oo

A solution of 4-(1H-indol-5-yloxy)-6b-methyl-5,8-dihydro-6H-pyridoyl3,4-4|pyrimidine-7-carboxylic acid tert-butyl ether (210 mg, 0.55 mmol) , KDI (179 mg, 1.10 mmol), TEA (230 μl, 1.65 mmol), and

DMF (5 mL) was stirred at RT for 1 h, then 5-tert-butyl-2H-pyrazole-Z-ylamine (77 mg, 0.55 mmol) and 4-pyrrolidinepyridine (16.4 mg, 0.11 mmol) were added. ). After 24 hours the reaction mixture is concentrated in a vacuum and purified with the help of KFC (5-90 96 E(OAc/heptane) and the desired compound is obtained. MS (IER) t/2 546.3 (M--1). 51-8. (5- Tert-butyl-2H-pyrazol-3-yl)-amide (g)-5-(b-methyl-5,6,7,8-tetrahydropyridoyl3,4-4|pyrimidin-4-yloxy)-indol-1- carboxylic acid.

Mao Xi -

M. mo LN rea

M o nn

N

4-(/1-(5-tert-butyl-2H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy|-6-methyl-5,8-dihydro-6bH-pyrido/ 3,4-4|pyrimidine-7-carboxylic acid (300 mg, 0.55 mmol), DCM (5 ml) and

TFC (5 ml) is stirred at CT for 2 h. Then the solution is concentrated and the residue is purified using semi-preparative HPLC (C18; 10-100 95 ACN/NgO with the addition of 0.195 MNAOH) and the desired compound is obtained. MS (IER) t/: 446.2 (M--1); "H NMR (400 MHz, Meob) b frequency/million 8.37 (5.1

H), 8.32 (a, 9-8.8 Gu, 1 H), 7.88 (y, 2-3.5 Hz, 1 H), 7.38 (y, 9-2.3 Hz, 1 H), 7.08 (yes, 9-91, 2.3 Hz, 1 H), 6.71 (9, 9-3.8 Hz, 1 H), 6.38 (Brg. 5., 1 H), 6.06 (bBg. 5., 1 H), 4.00 (a, 9-61 Hz, 2 H), 3.05 - 3.15 (t, 1 H), 3.00 (aa , 9-17.2, 3.5 Hz, 1 N), 2.47 (yes, 2-17.2, 10.4 Hz, 1 N), 1.36 (5, 9 N), 1.34 (a, U-6.3 Hz, Z H).

The following compounds are obtained by a similar method.

SHCI Structure/chemical name "H NMR (400 MHz) Me Ai t/h

Ma o X (Meor) 5 parts/million 8.37 (5, 1 H), and Mn 8.32 (a, U-8.8 Hz, 1 H), 7.88 (a,

M U. z-d uU-3.5 Hz, 1 H), 7.38 (y, 9-2.3 Hz, 1 H), 7.08 (da, 9U-9.1, 2.3 Hz , 1 N), 951 M on 6.71 (94, 923.8 Hz, 1 NU, 6.37 (5, 1 432

Н H), 3.96 (5.2 H), 3.19 (Hi, 9U-5.9 Hz, (b-tert-butyl-2H-pyrazol-3-yl)-amide 5-|2 H) . )-indole-1-carboxylic acid (meor) 5 parts/million 8.32 - 8.40

M. 0 (t, 2 H), 7.92 (y, 9U-3.8 Hz, 1 H), "more If; i 7.73 (9, 92-76 Hz, 2 H), 7.46 (uh,

M. and M MN 9U-7.6 Hz, 2 N), 7.34 - 7.41 (t, 2

M H), 7.10 (yes, U-9.0,2.4 Hz, 1 H), 51-0 oh 6.89 (bg. 8., 1 H), 6.73 (9, 4- 3.5 452 h HC, 1 H), 3.94 (5.2 H), 3.18 (h, (5-phenyl-2H-pyrazol-3-yl)-amide 5-n Hz, 2 H) .

IS

(meor) 5 parts/million 8.31 - 8.40 "still; (t, 2 H), 7.91 (a, 9-3.5 Hz, 1 H), t s If; and 7.15 (ad, 9-86, 5.3 Hz, 2 N), 7.40

M. is M MH (a, 9-2.3 Hz, 1 H), 7.20 (I, 2-8.8 51-E ХУ M Hz, 2 H), 7.10 (aa, 9-91 , 2.3 Hz, 470.1

M 1 H), 6.86 (Bg. 5., 1 H), 6.73 (y, y o nn 93.8 HZ, 1 H), 3.94 (5.2 H), 3.18

I I I I (i, 9-5.8 Hz, 2 H), 2.88 (I, 9U-5.7

15-(4-Fluorophenyl)-2H-pyrazole-3-yl|-amide Hz, 2H). 5-(5,6,7,8-tetrahydropyridoyi3,4-d9|pyrimidin-4-yloxy)-indole-1-carboxylic acid

IS

(DMSO-dv) b frequency/million 13.10 (y, y-2.5 Hz, 1 N), 10.77 (Bg. 5., 1 N),

M fi; 8.40 (5, 1 H), 8.33 (y, 9-91 Hz, 1 (y and H), 8.20 (rg. v., 1 H), 7.65 (a,

M. M. MN 9U-7.8 Hz, 2 H), 7.52 (d, 9-7.6 Hz, 51-E rya M 1 H), 7.43 (y, 2-23 Hz, 1 H), 7 ,20 470.2

M o nn (a, 9-16.2 Hz, 1 H), 7.11 (aa,

H 9-91, 2.3 Hz, 2 H), 6.74 (y, 9U-3,3 (5-(3-fluorophenyl)-2H-pyrazol-3-ylI-amide | HC, 1 H), 3.82 (5.2 H), 3.04 (I, 5-(5,6,7,8-tetrahydropyridoyi3,4-Y-5.7 Hz, 2 H), 2.73 (I, 925, 3 Hz, 2 α|pyrimidin-4-yloxy)-indole-1-H)carboxylic acid

Vi (DMSO-4v) 6 ppm 13.09 (bBg. 5., 1 N), 10.76 (bBg. 5., 1 N), 8.40

M i); cx (5, 1 H), 8.33 (y, 9-8.8 Hz, 1 H), i.e. If; du 8.20 (a, 9-30 Hz, 1 H), 7.72 - va i M MH 7.79 (t, 2 H), 7.63--7.70 (t, 2 5319 re М H ), 7.43 (y, 90-2.3 Hz, 1 N), 7.11'

M o nn (aa, 9U-9.0, 2.4 HZ, 1 H), 6.99 (Bg.

H 5.1 H), 6.74 (a, 2-38 Hz, 1 H), (5-(4-bromophenyl)-2H-pyrazol-3-ylI-amide | 3.83 (5, 2 H ), 3.04 (I, U-5.8 Hz, 2 5-(5,6,7,8-tetrahydropyrido|3,4-HO), 2.73 (, 9U-5.6 Hz, 2 H d9|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid

SI

(meor) 5 parts/million 8.32 - 8.40 "still (t, 2 H), 7.92 (y, 9-3.7 Hz, 1 H), y Xe X 7.13 (a, 9-81 Hz, 2 N), 7.47 (a,

M. is M t 98.3 Hz, 2 N), 7.40 (y, 9-21 Hz, 51-N X. zd 1 N), 7.11 (da, 9U-9.0, 2.3 Hz, 1 N), 486.1

M 6.96 (brg. 5., 1 H), 6.74 (0.95-3.5 and o nn HC, 1 H), 3.95 (5.2 H), 3.19 (i,

I I I I 925.9 Hz, 2 H), 2.89 (Her, 9-5.7 Hz, 2

15-(4-chlorophenyl)-2H-pyrazol-3-yl|-amide H). 5-(5,6,7,8-tetrahydropyridoyi3,4-d9|pyrimidin-4-yloxy)-indole-1-carboxylic acid (9) (DMSO-dv) 6 parts per million 13.12 (Bg.

Me and; 8.1 H), 10.77 (bg. 5., 1 H), 8.40 (y and (5, 1 H), 8.33 (y, 9-8.8 Hz, 1 H),

M mo u lH 8.20 (Bg. 5., 1 H), 7.89 (in, 1 H), 51-I rya M 7.77 (a, 9-78 Hz, 1 H), 7.38 - 486.1

M o nn 7.58 (t, Z H), 7.11 (da, U-9.0, 2.4

H Hz, 2 H), 6.73 (y, 9U-3.5 Hz, 1 H), (5-(3-chlorophenyl)-2H-pyrazol-3-ylI-amide | 3.82 (5, 2 H), 3.03 (I, 925.8 Hz, 2 5-(5,6,7,8-tetrahydropyrido|3,4- H), 2.72 (, U-5.7 Hz, 2 H) d9|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid (DMSO-dv) 6 ppm 8.42 (5.1

M y; Н), 8.29 (а, 9-8.8 Hz, 1 Н), 8.10 ХХ (а, 9-3.5 Hz, 1 Н), 7.81 (а, 9-71

M. 2 M zl Hz, 2 N), 7.38 - 7.48 (t, Z H), 51-y rya M 7.31 (5 9-7.3 Hz, 1 N), 7.12 ( yes, 466.1

M o nn 99.0, 2.4 Hz, 1 N), 6.80 (y, 9U-3.5

H Hz, 1 H), 6.77 (5.1 H), 3.88 (5.2 (2-methyl-5-phenyl-2H-pyrazol-3-yl)-amide | H), 3.81 (5, Z H), 3.09 (I, Y-5.8 Hz, 5-(5,6,7,8-tetrahydropyridoiZ3,4- 2 H), 2.76 (bg. 5.,2 H d9|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid

M i); M (mMeOb) 5 parts/million 8.64 (i,

That's If; ac 9-2.0 Hz, 1 N), 8.37 (5, 1 N), 8.33

M. M - (a, U-8.8 Hz, 1 N), 8.18 (a, 9U-1.0 rya Hz, 1 N), 8.03 (5, 1 N), 7.92 ( y, 51-K M o nn 9U-3.5 Hz, 1 H), 7.40 (a, 9-23 Gu, 4011

Hn 1 H), 7.10 (yes, 9-9,1,2,3 Hz, 1 H), (B-methylpyridin-Z-yl)-amide 5-(5,6,7,8- | 6.74 (y, Y-3.0 Hu, 1 H), 3.95 (5.2 tetrahydropyrido|3,4-4|pyrimidine-4-NU, 3.18 (y, Y-5.9 Hu, 2 H ), 2.88 (i, yloxy)-indole-1-carboxylic acid 5.8 Hz, 2 H), 2.41 (5, C H). "more; Ox (DMSO-dv) b parts/million 13.65 (bBg. and - x in 5., 1 H), 8.40 (5, 1 H), 8.91 (a,

M. Zh M I M 3-8.8 Hz, 1 H), 8.17 (a, 9-38 Gu,

Khm M 1 H), 7.42 (a, 9-2.3 Hz, 1 H), 7.11 (ai, 9U-9.0, 2.4 Hz, 1 H), 7.00 (Bg. 9171 M o n 5.1 N), 6.73 (a, 9-3.5 Hz, 1 M), 48 o 4.33 (4, 9-7.2 Hz, 2 N), 3.83 (5.2 ethyl ether 5-15-(5,6,7,8-H), 3.04 (y, y5.8 Hz, 2 H), 2.73 (5 tetrahydropyridoyY3,4-4|pyrimidine- 4-y-5.4 Hz, 2 H), 1.33 (i, 9-71 Hz, C yloxy)-indole-1-carbonyl|-amino)-1 H- n). pyrazole-3-carboxylic acid

Enantiomers are separated using chiral HPLC (column IA, 2:8 heptane/gOnH)

E M-1: (MmeOb) b freq./million o grAK 8.32 -- 8.47 (t, 2 H), 7.88 (4,

Mach X 3-3.8 Hz, 1 N), 7.39 (y, 9-23 Gu, (y МН 1), 7.10 (da, 9-91,2.3 Hz, 1 N),

М M 3 6.74 (a, 9-3.8 Hz, 1 N), 6.51 (5, 1 r N), 3.87 - 4.07 (t, 2 N), 3.05 -

M o nn 3.17 (t, 1 H), 3.00 (ai, 9U-16.9,

H 3.68 Hz, 1 H), 2.39 - 2.56 (t, 1 H), 51-M | M-1: (b-trifluoromethyl-1H-pyrazol-3-yl)- | 1.34 (a, 9U-6.3 Hz, Z H); chiral 458.0 amide (w)-5-(6-methyl-5,6,7,8- HPLC H-20.6 min. tetrahydropyridoyi3,4-4|pyrimidine-4- M-2: (MeOB) b parts per million of yloxy)-indole-1-carboxylic acid 8.29 - 8.47 (t, 2 H), 7.88 (y,

M-2: (b-trifluoromethyl-1H-pyrazol-3-yl)-|9U-3.8 Hz, 1 H), 7.39 (y, 952.3 Hz, amide (-)-5-(b -methyl-5,6,7,8-tetrahydro- (1 H), 7,10 (ad, 9-91, 2.3 Hz, 1 H), pyridoyi3,4-4|pyrimidin-4-yloxy)- indole-1-| 6.73 (y, 9-3.5 Hz, 1 H), 6.51 (5, 1 carboxylic acid H), 3.92 - 4.05 (t, 2 H), 3.05 - 3.18 (t, 1 H), 3.00 (ai, 9U-17.3, 3.7 Hz, 1 H), 2.40 - 2.58 (t, 1 H), 1.34 (a, 9U- 6.3 Hu, Z H); chiral

TOP OF KE29.7 min.

Example 52

B5B2-A. Tert-butyl ether (xt)-6-methyl-4-(1-(3-trifluoromethylphenyl-carbamoyl)-1H-indol-5-yloxy|- 5,8-dihydro-6H-pyridoyi3,4-4|Ipyrimidine- 7-carboxylic acid.

M.O ES vav;

M. u

M (in) N

J

A solution of 4-(1H-indol-5-yloxy)-6b-methyl-5,8-dihydro-6H-pyridoyl3,4-4|pyrimidine-7-carboxylic acid tert-butyl ether (150 mg, 0.39 mmol) and THF (5 mL) is cooled to 0 °C. Man (23.6 mg, 0.59 mmol, 60 95 in mineral oil) is added to it, then 3-trifluoromethyl isocyanate (0.11 mL, 0.79 mmol) and the reaction mixture is allowed to warm to room temperature. After the end of the reaction, according to LCMS, the mixture is partitioned between DCM and a buffer solution with pH 7. The organic layer is separated, dried over anhydrous Mag5O4 and concentrated. The crude residue is purified using KFC (5-90 96 EOAs/ heptane) and obtain the desired compound. MS (IER) t/2 568.3 (M.n1).

B2-8. B52-8-1: (3-Trifluoromethylphenyl)-amide (-)-(5)-5-(6-methyl-5,6,7,8-tetrahydropyridoi3,4-9|pyrimidin-4-yloxy)-indole -1-carboxylic acid and 52-8-2: (3-trifluoromethylphenyl)-amide (g)-I-5-(6-methyl-5,6,7,8-tetrahydropyridoyi3,4-4|Ipyrimidine-4- yloxy)-indole-1-carboxylic acid. se; ES ev;

M. 22 u

M (in) N

N

Solution of tert-butyl ether b-methyl-4-|1-(3-trifluoromethylphenyl-carbamoyl)-1H-indol-5-yloxy|- 5,8-dihydro-6H-pyridoi|3,4-4|Ipyrimidine- 7-carboxylic acid (74 mg, 0.13 mmol), DCM (5 mL) and TFA (5 mL) were stirred at RT for 2 h. Then the solution is concentrated in a vacuum and the residue is purified using semi-preparative HPLC (C18; 10-100 95 ACN/H2gO with the addition of 0.195 MNAOH) and the racemic desired compound is obtained. Then the racemate is separated using chiral liquid chromatography (SpigaIrac Ar column; heptane/Egyun 1:1) and 2 corresponding enantiomers B-1 and

B-2. 52-8-1: A compound with a Ki value of 5.5 min is interpreted as the (w)-(5)-enantiomer; MS (IER) t/2 468.3 (M--1); "H NMR (400 MHz, mMeob) b frequency/million 8.37 (5, 1 H), 8.32 (y, U-8.84 Hz, 1 H), 8.05 (5, 1 H) . ), 7.43 (a, 9-7.58 Hz, 1 H), 7.38 (a, 9-1.77 Hz, 1 H), 7.08 (ad, 2-8.97, 1, 89 Hu, 1 H), 6.72 (a, 9-3.54 Hu, 1 H), 3.92 -4.08 (t, 2 H), 3.04 - 3.15 (t, 1 H ), 2.98 (09, 9U-17.18, 3.28 Gu, 1 H), 2.46 (da, U-16.93, 10.61 Hz, 1 H), 1.33 (a, 9U-6.32 Hu, Z H). 52-8-2: The compound with a Ki value of 6.7 min is interpreted as (-)-I enantiomer; MS (PER) t/2 468, 2 (M--1); "H NMR (400 MHz, Meor) 5 ppm 8.37 (5, 1 H), 8.32 (y, U-8.84 Hz, 1 H), 8 .05 (5, 1

Н), 7.92 (0.9-3.79 Г, 1 Н), 7.89 (а, 9У-8.59 Hz, 1 Н), 7.56 (Й, У-7.96 Hz, 1 H), 7.44 (a, 2-7.83 Hz, 1 H), 7.39 (9, 9-2.27 Hz, 1 H), 7.09 (da, 9U-8.97, 2.40 Gu, 1 N), 6.73 (y, U-3.79 Hz, 1 N), 3.89 - 4.09 (t, 2 N), 3.05 - 3.16 (t, 1 H), 2.99 (aa, 9-17.18, 3.79 Hz, 1 H), 2.47 (aa, O-17.18, 10.36 Hz, 1 H), 1.34 ( a, 9U-6.57 Hz, Z H).

The following compounds are obtained by a similar method. 52-60. (3-Trifluoromethylphenyl)-amide (g)-4-fluoro-5-(b-methyl-5,6,7,8-tetrahydropyrido|3,4-4|pyrimidin-4-yloxy)-indole-1-carbon acid

IS

E.S

Ge) Z

Co

MO 2 in

M (in) N

N

MS (IER) t/2 486.1 (M--T1); "H NMR (400 MHz, meob) b frequency/million 8.58 (5.1 H), 8.31 (y, 9-8.84 Hz, 1

H), 8.25 (5.1 H), 8.01 -8.17 (t, 2 H), 7.76 (I, 9-7.96 Hz, 1 H), 7.63 (y, 9-7.58 Hz, 1 H), 7.37 (I, 9U-8.59 Hz, 1

H), 7.60 (a, 9-3.79 Hz, 1 H), 4.20 (a, 9U-5.05 Hz, 2 H), 3.29 (aaa, 9U-10.48, 6 ,32, 4.17 Hz, 1 N), 3.20 (aa,

U-17.18, 3.79 Hz, 1 H), 2.69 (yes, 9U-17.18, 10.36 Hz, 1 H), 1.53 (y, U-6.32 Hz, Z N).

Example 53 53-А. 53-A-1: Ethyl ether of (5)-2-methyl-5-oxo-1-((5)-1-phenylethyl)-piperidine-4-carboxylic acid and 53-A-2: Ethyl ether (K) -2-methyl-5-oxo-1-((5)-1-phenylethyl)-piperidine-4-carboxylic acid. (6) (6)

OO eyes

M (6) M (6) 53-A-1 53-A-2

It is obtained by a method similar to that described in example 50C, using in the method of example 50A chiral (-)-(5)-1-phenylethylamine instead of racemic 1-phenylethylamine.

Diastereoisomers A-1 and A-2 are separated using KFC (2.5 95 EAs/heptane). 53-A-1: MS (IER) t/2 290.2 (M-1); "H NMR (400 MHz, SOSI") b frequency/million 11.81 (5, 1 H), 7.18 - 7.37 (t, 5H), 4.16-4.27 (t, 2 H ), 3.70 (a, 9U-6.6 Hz, 1 N), 3.27 - 3.38 (t, 1 N), 2.82 - 3.13 (t, 2 N), 2.53 (yes,

9-15.5, 5.2 Hz, 1 H), 2.10 (yes, Y-15.5, 3.7 Hz, 1 H), 1.33 (a, Y-6.6 Hz, Z H), 1.30 (I, 2-71 Hz, Z H), 1.05 (a, 93-6.6 Hu, Z H). 53-A-2: MS (IER) t/2 290.2 (M-1); "H NMR (400 MHz, SOSI") b frequency/million 11.94 (5.1 N), 7.19 - 7.36 (t, 5 N), 4.13 - 4.29 (t, 2 H), 3.63 (a, 9U-6.6 Hz, 1 H), 3.09 - 3.52 (t, 2 H), 2.94 - 3.05 (t, 1 H), 2, 34 - 2.47 (t, 1 H), 1.94 (a, 9-15.4 Hz, 1 H), 1.34 (a, U-6.6 Hz, C H), 1.281, 9- 72 Hz, Z H), 0.90 (a, U-6.8 Hz, Z H). 53-8. 53-8-1: (5)-tert-butyl ether 4-(1H-indole-5 -yloxy)-6-methyl-5,8-dihydro-6H-pyridoyl3,4-α|pyrimidine-7-carboxylic acid and 53-8-2: (H)-tert-butyl ether 4-(1H-indole- 5-yloxy)-6-methyl-5,8-dihydro-6H-pyridoy3,4-

Phypyrimidine-7-carboxylic acid fo) M (c) I go

M. 2 M M. 22 M

Nn Nn

MO M ra 53-8-1 and 53-8-2

Enantiomers 53-8-1 and 53-8-2 are obtained, respectively, from the compound of example 53-A-1 and the compound of example 53-A-2, as described in example 50-Сс5. 53-8-1: MS (IER) t/2 381.1 (M--1). 53-8-2: MS (IER) t/2 381.1 (M--1).

The following compounds are obtained by a similar method. 53-Sab. 53-0-1: Tert-butyl ether (5)-4-(4-fluoro-1H-indol-5-yloxy)-6-methyl-5,8-dihydro-6H-pyridoyl3,4-d|Ipyrimidine- 7-carboxylic acid and 53-0-2: tert-butyl ether 1I-4-(4-fluoro-1H-indol-5-yloxy)-6-methyl-5,8-dihydro-6H-pyridoy|3,4 - α|pyrimidine-7-carboxylic acid

E E no) M. (c)

SOS co

Mi 2 M Mu M

Nn Nn

MO M oo 53-6-1 A 53-0-2

Enantiomers 53-0-1 and 53-0-2 are obtained, respectively, from the compound of example 53-A-1 and the compound of example 53-A-2, as described in example 50-H. 53-0-1: MS (IER) t/ 399.1 (M-n1). 53-6-2: MS (IER) t/ 397.2 (M-1).

Example 54 54-А. Tert-butyl ether (5)-4-11-(2-tert-butoxycarbonyl-5-(1-methylcyclopropyl)-2H-pyrazol-3-ylcarbamoyl|-1H-indol-5-yloxy)-b-methyl- 5,8-dihydro-6H-pyridoyi3,4-4|pyrimidine-7-carboxylic acid. av;

WITH

M. 2 mol umy MV mya o no uch i oso

Sodium hydride (0.024 g, 0.990 mmol; 60 95 in oil) is added to a solution of 4-(1H-indol-5-yloxy)-6-methyl-5,8-dihydro-6H-pyridoyl (5)-tert-butyl ether. ,4-4|pyrimidine-7-carboxylic acid, the compound of example 53-8-1 (0.126 g, 0.330 mmol) and DMF (7.5 ml) at RT. In 5 minutes. add 3-(1-methylcyclopropyl)-5-phenoxycarbonylaminopyrazole-1-carboxylic acid tert-butyl ether, compound of example 5-0 (0.178 g, 0.495 mmol). After 1 hour the reaction is stopped by adding a saturated aqueous solution of MNACI and then concentrated. The residue is purified using KFC (20-70 90 EAs/heptane).

MS (ER) t/2 644 2 (M-n1). 54-8. 15-(1-Methylcyclopropyl)-2H-pyrazol-3-yl|1-amide 5-((5)-6-methyl-5,6,7,8-tetrahydropyridoyl3,4-

Phipyrimidin-4-yloxy)-indole-1-carboxylic acid. (6) ee IF; AND

M. 2 Mol

Hmm wn m" on

N

A solution of tert-butyl ether (5)-4-11-(2-tert-butoxycarbonyl-5-(1-methylcyclopropyl)-2H-pyrazole-

3-ylcarbamoyl|-1H-indol-5-yloxy)-6-methyl-5,8-dihydro-6H-pyridoyl3,4-4|pyrimidine-7-carboxylic acid (0.212 g, 0.330 mmol), DCM (5 ml) and TFC (2 ml) are mixed at CT for 1 hour. The solution is concentrated in vacuo, transferred to MeonH and neutralized by adding a few drops of an aqueous solution of MNAOH. Then purified using semi-preparative HPLC (C18; 10-100 95

ACN/H2O with the addition of 0.1 95 MNAOH) and obtain the desired compound. MS (ER) t/2 4441 (MaА1); "N

NMR (400 MHz, DMSO-dv) 6 ppm 12.13 (bBg. 5., 1 N), 10.55 (5, 1 N), 8.40 (in, 1 N), 8.29 (a, 2-8.8 Hz, 1

H), 8.16 (a, 9-3.5 Hz, 1 H), 7.40 (a, 9-23 Hz, 1 H), 7.08 (aa, 9-91, 2.3 Hz, 1 H), 6.70 (a, 9-38 Hz, 1 H), 6.30 (c, 1 H), 3.76 - 3.98 (t, 2 H), 2.92 - 3.05 (t, 1 H), 2.85 (ad, U-16.5, 3.4 Hz, 1 H), 2.27 -2.40 (t, 1 H), 1.41 (5, Z H ), 1.22 (a, 2-6.3 Hz, with H), 0.89 - 0.97 (t, 2 H), 0.73 - 0.82 (t, 2 H).

The following compounds are obtained by a similar method.

ST stkuvennnenya | 00 yum TD

M. 0 (meob) 5 parts/million 8.51 (5.1 N), and t IF; X 8.34 (a, 9U-9.0 Hz, 1 H), 7.90 (y,

M. A M | /x 9U-3.8 Gu, 1 H), 7.41 (a, 9-21 Hz, 1 ra M H), 7.10 (da, 9U-9.0, 2.3 Hz, 1 H) , 54-6 M about them H 6.72 (9.9-3.7 Hz, 1 H), 6.28 (5.1 H), 4441

H 3.73 - 3.88 (t, 1 H), 2.86 (aa, (5-(1-methylcyclopropyl)-2H-pyrazole-|9717.9, 10.7 Gu, 1 NU, 1.59 (y, 926.4 3-yl-amide 5-(I-B-methyl-5,6,7,8-Hz, Z H), 1.46 (5, Z H), 0.92 -1, 03 tetrahydropyrido/3,4-a|pyrimidine-4-|(7. 2 NU, 0.75 - 0.88 (t, 2 H).yloxy)-indole-1-carboxylic acid.

M o (meob) b frequency/million 8.52 (5, 1 N), "Me If; | 8.35 (y, 4-9.0 Hz, 1 N), 7.91 (4,

M. Zh M | x 9-3.7 Gu, 1 H), 7.41 (a, 9-23 Hz, 1 r М H), 7.10 (da, 9U-9.0, 2.4 Hz, 1 H), 54-0 o their n 6.73 (9, 9-3.7 Hz, 1 N), 6.39 (5.1 N), 485.1 their 3.72 - 3.86 (t, 1 N) . 2.02 (t, 2 H), 1.53 - 1.62 (t, 6 H).tetrahydropyridoyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

M i); (DMSO-dv) 6 ppm 12.21 (bBg. 5., (and If; - 1 N), 10.56 (v, 1 N), 8.39 (v, 1 N),

M. M MN 8.29 (a, 9-91 Hz, 1 H), 8.16 (4, p M 9-3.5 Hz, 1 H), 7.41 (a, 9-23 Hz, 1 54-E M o nn H), 7.08 (aa, 9-91, 2.3 Hz, 1 H), 418.2

H 6.70 (9.9-3.5 Hz, 1 H), 6.34 (5.1 H), (B-isopropyl-1H-pyrazol-3-yl)-amide 5- | 2.81 (5.2 N), 2.87 - 3.07 (t, C H), (5,6,7,8-tetrahydropyridoi|3,4- 2.12 (025.6 Hz, 2 N), 1.25 (a, 9-68 a|pyrimidin-4-yloxy)-indole-1-Hz, 6 H). carboxylic acid.

o (DMSO-yv) 6 ppm 12.23 (bg. 5., ge X 1 N), 10.54 (Bg. 8., 1 N), 8.39 (v, 1 te H), 8.28 (a, 9-9.1 Hz, 1 N), 8.15 (a,

M U. eri U-3.3 Hz, 1 H), 7.40 (a, 9-2.3 Hz, 1

M H), 7.08 (ad, 9-9.0, 2.4 Hz, 1 H), according to M o n 6.69 (a, 4-38 Hz. 1 H), b22 (bg 51007162

H H), 3.81 (5.2 H), 3.03 (1.9-5.8 Hz, 2 (5-cyclopropyl-1 H-pyrazol-3-yl)-amide | H), 2, 72 (i, 9U-5.6 Hz, 2 H), 1.82 - 5-(5,6,7,8-tetrahydropyridoi3,4- 2.00 (t, 1 H), 0.90 -1, 01 (t, 2 H), d9|Ipyrimidin-4-yloxy)-indol-1- 0.65 - 0.76 (t, 2 H). carboxylic acid.

E o (MeOr) 5 parts/million 8.39 (5, 1 N), he X 8.12 (0, 9-8,84 Hz, 1 N), 7.89 (a,

M 93.79 Hz, 1 N), 7.17 (ai, 9U-8.84,

M M | M 7.58 Hz, 1 H), 6.80 (y, 9U-3.28 Hz, 1 re H H), 6.30 (rg. v., 1 H), 4.02 (a, U- 6.532 54-44 M o nn Hz, 2 N), 3.13 (give, 9-10.23, 6.44, 462.1

H 3.79 Hz, 1 H), 3.03 (ai, 9-17,18,3,28 (5-(1-methylcyclopropyl)-2H-pyrazole- | Hz, 1 H), 2.55 (ai , 9U-17,18, 10,36

3-yl|-amide (g)-4-fluoro-5-(6-methyl-H, 1 H), 1.46 (5, 3 H), 1.35 (y, 5,6,7,8 -tetrahydropyridoyiZ,4- 3-6.32 Hz, C H), 0.91 - 1.04 (t, 2 d9|Ipyrimidin-4-yloxy)-indole-1- H), 0.74 - 0.88 (t, 2 N). carboxylic acid

E o (MeOb) 5 parts/million 8.39 (5, 1 N), gai X 8.12 (a, 9-8.84 Hz, 1 N), 7.89 (a, tm 93.79 Hz , 1 H), 7.17 (ai, 9U-8.84,

M M I M 7.58 Hz, 1 H), 6.80 (y, 9U-3.28 Hz, 1 .,, rya H H), 6.30 (rg. v., 1 H), 4, 02 (a, U-6.532 54-N MO 7 o nn Hz, 2 N), 3.13 (give, 9-10.23, 6.44, 462.1

H 3.79 Hz, 1 H), 3.03 (ai, 9-17,18,3,28 4-fluoro-(5-(1-methylcyclo-propyl)-2H- | Hz, 1 H), 2 .55 (yes, 9U-17.18, 10.36 pyrazol-3-yl|-amide 5-((5)-6-methyl-HC, 1 H), 1.46 (5, C H), 1 ...

Pyrimidin-4-yloxy)-indol-1-H), 0.74 - 0.88 (t, 2 H). carboxylic acid.

E o (MeOr) 5 parts/million 8.39 (5, 1 H), he X 8.12 (a, 9-8.84 Hz, 1 H), 7.89 (a, tm 93.79 Hz , 1 H), 7.17 (ai, 9U-8.84,

M M | M 7.58 Hz, 1 H), 6.80 (y, 9U-3.28 Hz, 1 re H H), 6.30 (rg. v., 1 H), 4.02 (a, U- 6,532

Ba4-I M o nn Hz, 2 H), 3.13 (give, 9-10.23, 6.44, 462.1

H 3.79 Hz, 1 H), 3.03 (yes, 9-17.18, 4-fluoro-(5-(1-methyl-cyclopropyl)-2H- | 3.28 Hz, 1 H), 2 ... 35 (a, 5,6,7,8-tetrahydropyridoyiZ,4-3-6,32 Hz, Z H), 0.91 - 1.04 (t, 2 a|pyrimidin-4-yloxy)-indole-1 - H), 0.74 - 0.88 (t, 2 H). carboxylic acid.

E more) (MeOr) 5 ppm 8.38 (5.1 N),

Ty t x X 8.12 (a, 9-8.84 Hz, 1 H), 7.88 (a,

M. Zh M at 93.79 Hz, 1 H), 7.17 (ai, 9U-8.84,

M 7.58 Hz, 1 H), 6.80 (a, 9U-3.79 Hz, 1 5a-y M o H H), 6.31 (bg. 5., 1 H), 3.96 ( 5, 2 H), 48

H 3.19 (I, 9-5.94 Hz, 2 H), 2.91 (i, 4-fluoro-(5-(1-methyl-cyclopropyl)-2H- 575.68 Hz, 2 H), 1.46 (5, C H), 0.92 - pyrazole-3-yl-amide 5-(5,6,7,8- 1.03 (t, 2 H), 0.76 - 0.86 ( t, 2 N). tetrahydropyrido/Z3,4-4|pyrimidine-4-

00110 (yloxy)indole-y-carboxylic acids. | b '7777777777777777777Й7117121

IS

M "Sa (DMSO-dv) 6 parts per million 12.17 (bBg. 5.,

Ty r 1 H), 10.71 (Bg. 5., 1 H), 8.56 (5, 1 wk M and H), 8.20 (4, 9-3.54 HC, 1 H), 8 ,12 (4, y-8.84 Hz, 1 H), 7.27 (a, 9-7.83 Gu,

Zk M vy 1n),vva(a, ze gts Nv., , (551H),4521(5,2H),410 (5,2H), (5-01-methylcyclopropyl)-1H-pyrazole-1, 44 (in, C H), 0.85 - 1.01 (t, 2 H),

Z-yl|amide 5-(6,7-dihydro-5H- 0.70 - 0.85 (t, 2 H).pyrrolo|3,4-4|pyrimidin-4-yloxy)-4-fluoroindole-1 -carboxylic acid. (c) (DMSO-ав) b freq./million 12.27 (bg. 5., o 1 N), 10.62 (5, 1 N), 8.55 (5, 1 N), che X 8 ... ,

BA M 1 Nu), 71199, 9-8,84,227 HC, 4602

M Hm H 6.71 (9, 9-3.54 Hz, 1 H), 6.39 (5, 1 ;

N o n H), 3.96 - 4.26 (t, 4 H), 3.60 - 3.78

15-(4-methyltetrahydropyran-4-yl)-2H-(t, 2H), 3.46 (dav, 9-11.49, 8.46, pyrazol-3-yl1-amide 5-(6.7 -dihydro-5H- | 2.78 Hz, 2 H), 2.01 (t, 2 H), 1.63 (t, pyrrolo!|3,4-4|pyrimidin-4-yloxy)- 2 H), 1 ,29 (5, Z H). indole-1-carboxylic acid. (DMSO-av) b frequent./million 12.24 (bBg. 5.,

M fe; 1 N), 10.56 (5, 1 N), 8.55 (5, 1 N),

Y x 8.29 (9, 9-9.09 HZ, 1 H), 8.17 (4, vk M | tsu 9-3.54 HZ, 1 H), 7.44 (y, 9-2, 27 Hz, 1 NU, 7.12 (9, 9-9.09 Hz, 1 H), 6.70 5a-M M o H (9, 9-3.54 Hz, 1 NU, 6.22 (5 , 1 H), 402 ... 14.07 -4.13 (t, 4 H), 1.91 (da, (5-cyclopropyl-2H-pyrazol-3-yl)-amide -13.39, 3 .54 Hz, 1 N), 0.95 (yes, 5-(6,7-dihydro-oH-pyrrolo|3,4- 4-8.34, 2.27 Hz, 2 N), 0.70 - 0.74 d9|Ipyrimidin-4-yloxy)-indol-1-y (t, 2 N).

Se IF; | 1 N), 10.58 (5, 1 N), 8.55 (8, 1 N),

M. and M rom 8.30 (a, 9-9.09 Hz, 1 H), 8.18 (4, ra M 9-3.79 Hz, 1 H), 7.44 (d, 9-2 ,27 Hz, 5A-M M o i H 1 H),7,11(9a,9-8,59,2,53HZ,1 NN) 4041

H 6.71 (a, 9-3.79 Hz, 1 H), 6.34 (5, 1 (5-isopropyl-2H-pyrazol-3-yl)-amide 5-|H), 4.07 - 4.12 (t, 2 H), 4.09 (4, (6,7-dihydro-5H-pyrrolo!|3,4- U-14.15 Hz, 2 H), 2.95 (y, 9U -7.07 Hz, d9|Ipyrimidin-4-yloxy)-indole-1-1 H), 1.25 (a, 9-6.82 Hz, 6 H). carboxylic acid. "more (DMSO-dv) 6 parts/million 12.13 (5, and M: x 1N), 10.57 (5, 1 N), 8.55 (5, 1 N), va IF; ZM 8 .29 (a, 9-9.09 Hz, 1 N), 8.17 (4,

M 9-3.79 Hz, 1 H), 7.44 (y, 9-2.27 Hz, 5A-O M X-m H 1 Nu), 7.11 (а9.9-9.09.2 , 53 Hz, 1 I 4162

N o nn 6.71 (a, 9-3.54 Hz, 1 H), 6.29 (5, 1 (5-(1-methylcyclopropyl)-2H-pyrazole- | H), 4.09 (j, 9U-12.63 Hz, 4 N), 1.41

3-ylI-amide 5-(6,7-dihydro-5H-pyrrolo|3,4| (5, C H), 0.91-0.93 (t, 2 H), 0.74- a|pyrimidine -4-yloxy)-indole-1- 0.78 (t.2 H). carboxylic acid

M HF) (DMSO-dv) b freq./million 10.11 (5.1 "Me If; in NU, 8.54 (5.1 H), 8.43 (a, 9-9.09 HZ,

M. and M in 1 N), 8.19 (a, 93.79 Hz, 1 N), 7.51

M (d, 9-2.53 Hz, 2 H), 7.22 (ad, 9-8.97,

ZR M o H 2dogts1 Nv -ve0(ty 2), 0000

H 4.21 (952.15 Hz, 2 H), 4.14 (i, (B-(1-methylcyclobutyl)-2H-pyrazole-3-|.)-2.27 Hz, 2 H), 3, 48 (5.2 H), 2.78 - ylI-amide 5-(6,7-dihydro-5H-pyrrolo/|3,4- | 2.82 (t, 2 H), 1.41 - 1, 52 (t, 5 N). d9|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid o (DMSO-yv) 6 parts/million 12.13 (bBg. 5., ge IF; 1 N), 10.55 (in, 1 N), 8.40 (5, 1 N), zm 8.29 (a, U-8.8 Hz, 1 N), 8.16 (4,

S U. I M 9EZ,8 Hz, 1 H), 7.41 (a, 9-2.3 Hz, 1

M NN H), 7.08 (yes, 9-9.0,2.4 Hz, 1 H), 5a-0 M o n 6.70 (a.94-3.5 Hz H), v29(5 ,1 NN) 0002

H 3.84 (5.2 H), 3.05 (I, 9-58 HC, 2 H), (5-(1-methylcyclopropyl)-2H-pyrazole-|2.69 - 2.78 (t, 2 H), 1.41 (5, C H),

Z-yl|-amide 5-(5,6,7,8- 1.25 (Bg. 5.,2 H), 0.89 -0.97 (t, 2 tetrahydropyrido|Z,4-a4|pyrimidine -4-|H).yloxy)-indole-1-carboxylic acid

Mu i); (DMSO-yv) b frequency/million 10.56 (5.1 and If; du H), 8.40 (5.1 H), 8.29 (y, 9-91 Hz, 1

M. M MN H), 8.16 (4, 9-3.8 Hz, 1 H), 7.40 (4, rya M U-2.3 Hz, 1 H), 7.08 (yes, U -9.0, 2.4 54-8 M o nn Hz, 1 N), 6.70 (a, 9-3.5 Hz, 1 N), 432.2

H 6.34 (bBg. 5., 1 H), 3.79 - 3.98 (t, 2 (B-isopropyl-1 H-pyrazol-3-yl)-amide 5- | H), 2.89 - 3.04 (t, 2 H), 2.85 (yes, ((5)-6-methyl-5,6,7,8- 916.8, 3.4 Hz, 1 H), 2.27 - 2.39 (t, tetrahydropyrido|3,4-a4|)pyrimidine-4-. |1 H), 1.17 - 1.30 (t, 9 H)yloxy)-indole-1-carboxylic acid

M i); x (DMSO-yv) b freq./million 10.56 (5.1

That's If; d H), 8.40 (5, 1 H), 8.29 (y, 9-91 Hz, 1

M. 2 M MH H), 8.16 (a, 9-3.5 Hz, 1 H), 7.40 (a, p M 92.5 Hz, 1 H), 7.08 (ad, 9U- 9.0, 2.4 54-5 M o nn Hz, 1 N), 6.70 (a, 9U-3.8 Hz, 1 N), 432.2

H 6.34 (5, 1 H), 3.77 - 3.98 (t, 2 H), (B-isopropyl-1H-pyrazol-3-yl)-amide 5- | 2.90 - 3.03 (t, 2 H), 2.85 (ad, (B)-6-methyl-5,6,7,8- 916.9, 3.5 Hz, 1 H), 2 .27 - 2.39 (t, tetrahydropyrido|3,4-a|pyrimidine-4- | 1 H), 1.16 - 1.33 (t, 9 H) yloxy)-indole-1-carboxylic acid pe o x CE, (DMSO-b) b frequent./million 12.79 (bBg. 5.,

MH 1 H), 10.72 (Bu. 5., 1 H), 8.40 (5.1

M M s H), 8.29 (y, 9-9.0 Hz, 1 H), 8.16 (bBg.

BA-T rya 5., 1 H), 7.42 (a, 9-1.8 Hz, 1 H), 7.10 4841

M o nn (a, 9-10.9 Hz, 1 N), 6.60 -6.77 (t, 2 '

H H), 3.84 (rg. 5., 2 H), 3.06 (rg. 5., 2

I5-(1-trifluoromethyl-cyclopropyl)-1 H-| H), 2.74 (ru. v., 2 H), 1.39 (rg. 5., 2 pyrazol-3-yl|-amide 5-(5,6,7,8- H), 1, 29 (re. 5., 2 H) tetrahydropyridoyi3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid

(c) ha If; r (meorb) 5 parts/million 8.53 (5.1 N),

M. m s 8.33 (a, 4-8.84 HZ, 1 N), 7.90 (4,

Uk back 9Ch-3.79 Hz, 1 N), 7.67 (a, 9-2.53 Hz,

M 1 NU, 7.42 (0.9-2.27 Hz, 1 N), 711 540 N on (cha, 9-8.97, 2.40 Hz, 1 N), 6.71 (a, yavi (1-tert-butyl-1H-pyrazol-3-yl)-amide 5-|)-3.79 Hz, 1 H), 6.55 (y, 9-2.27 Hz, (6,7-dihydro -5H-pyrroloi3,4- 1), 4.19 (a, Y-7.83 Hz, 4 H), 1.59 a|pyrimidin-4-yloxy)-indole-1- (5.9 H) carboxylic acid acid (DMSO-dv) 6 ppm 8.40 (5, 1 mi H), 8.30 (4, 4-9.09 Hz, 1 H), 8.20 (4,

That's If; d r 9Ch-3.79 Hz, 1 N), 7.78 (a, 9-2.27 Hz,

M. M rai; 1 NU, 7.40 (4, U-2.53 Hz, 1 H), 7.08 Ucha (yes, 2-8.97, 2.40 Hz, 1 H), 6.70 (4,

Bi mon 9Ch-3.79 Hz, 1 H), 6.52 (a, 9-2.53 Hz, 4461

H 1 H), 3.87 (4, 4-6.82 Hz, 2 H), 2.96 ' (1-tert-butyl-1H-pyrazol-3-yl)-amide 5-| (aa, U-10.36, 6.06, 4.29 HC, 1 H), ((8)-β-methyl-5,6,7,8- 2.85 (ai, 9-16.80 . -carboxylic acid rya (5.9 NU, 1.21 (0.9-6.32 Hz, Z

M. ,0 ty He If; He r (DMSO-dv) 6 parts/million 10.57 (5.1

M. A M M H), 8.39 (5.1 H), 8.28 (y, U-8.84 Hz, re M 1 H), 8.15 (y, 9-3.79 Hz, 1 H), 7.41 (a, y9-2.27 Hz, 1 H), 7.08 (aa, 9-8.97,

ZAM and it 2.0 Hz, 1 H), 6.70(a,9-3.79 Hz, 00000 (1,5-dimethyl-1H-pyrazol-3-yl)-amide 5- | M); 6.34 (5, 1 H), 3.81 (5, 2 H), 3.68 (5,6,7,8-tetrahydropyridoi|3,4-(5, C H), 3.03 (and , 9-5.81 Hz, 2 H), a|pyrimidin-4-yloxy)-indole-1- 2.12 (6 9-5.68 Hz, 2 H), 2.27 (5, C H) of carboxylic acid of higher density X Х (DMSO-dv) b parts/million 10.70 (5.1 ci r M rai; H), 8.39 (5.1 H), 8.30 (a, 4-8 .97 Hz, di 1 H), 8.20 (9, U-3.54 Hz, 1 H), 7.78

X-m (9, 9-2.27 Hz, 1 NU, 7.41 (4, U-2.53

BA-X M o n Hz, 1 N), 7.08 (aa, 9-8.97,2.40 Hz, 1. 432.0 tn), 6.70 (a, 9-3.03 Hz, 1 H), 6.52 (9, (1-tert-butyl-1H-pyrazol-3-yl)-amide 5-9-2.53 Hz, 1 H), 3.81 (5, 2 H), 3.03 (5,6,7,8-tetrahydropyrido(3,4- (6 3-5.94 Hz, 2 H), 2.72 (i, 9-5.68 a|pyrimidin-4-yloxy) -indole-1-HC, 2 N), 1.54 (5, 9 N). a, 3-8.84 Hz, 1 N), 7.88 (4,

M. M s m- Ch-3.79 Hz, 1 N), 7.42 (y, 9-2.53 Hz, m ra 1 N), 7.11 (99, 9U-8.97, 2, 40 HC, 1 M), 5BA-U her at NN 6.71 (a, 9-3.54 HC, 1 H), 6.32 (5, 1 418.0 (1-isopropyl-5-methyl-1H -pyrazol-Z-yl)- Nu, 4.51 (va, 56.61, 6.44 Hz, 1 H), ! " ! 4.19 (j, 4-6.06 Hz, 4 H), 2 ,32 (5, C amide 5-(6,7-dihydro-5H-pyrroloi|3,4- H), 1,44 (a, U-6,82 Hz, 6 H) d9|Ipyrimidin-4-yloxy )-indole-1-shi ' ' c, and carboxylic acid (DMSO-d6) 5 parts/million 10.62 (5, 1

E X XK H), 8.39 (5, 1 H), 8.29 (a, 4-8.84 HZ,

M» IF; about 1 N), 8.19 (4, U-3.79 Hz, 1 N), 7.40 (9, 9-2.78 Hz, 1 N), 7.08 (49, U-8, 97, a ra, 2.40 Hz, 1 N), 6.69 (4, 9-3.03 Hz, 1 432.0

M o n H), 6.33 (5, 1 H), 4.48 (quintet,

H Ch-6.57 HC, 1 H), 3.81 (5.2 H), 3.02 (1-isopropyl-5-methyl-1H-pyrazol-3-yl)-| (i, 4-5.81 Hz, 2 H), 2.72 ( 9-5.56 amide 5-(5,6,7,8-tetrahydropyridoY3,4- | Hz, 2 H), 2.29 ( 5, C H), 1.38 (y, d9|Ipyrimidin-4-yloxy)-indole-1-9-6.57 Hz, 6 H). carboxylic acid o (DMSO-dv) 6 ppm 10.72 (5.1

E X X H), 8.39 (5.1 H), 8.30 (y, 9U-8.84 Hz,

S M paradise; 1 N), 8.19 (a, 9-3.79 Hz, 1 N), 7.73

XM zm (a, 9-2.27 Hz, 1 N), 7.41 (0.9-2.27

M Hz, 1 H), 7.08 (aa, 9U-8.97, 2.40 Hz, 1

B54-AA M On H), 6.70 (a, 9-3.79 Hz, 1 H), 6.51 (a, 418.0 . . . . 9-2.27 Hz, 1 H), 4.45 (activity, 9U-13.33, (1-isopropyl-1H-pyrazol-3-yl)-amide 5- 6.60 HZ, 1H), 3.81 (5, 2H), 3 ,03 (i, (5,6,7,8-tetrahydropyrido|3,4- 925,81 HZ, 2 H), 2,72 (, 24-5,68 HZ, 2 49|pyrimidin-4-yloxy) -indole-1-H), 1.44 (y, 9-6.57 Hz, 6 H). carboxylic acid

Mo c (DMSO-db) b freq./million 10.58 (4, g If; 2 91.26 Hz, 1 H), 8.55 (5, 1 H), 8.30

M. mo | M (4, 9-8.59 HZ, 1 H), 8.16 (4, U-3.54

M MM Hz, 1 NU, 7.44 (а, 9-2.27 Hz, 1 МН), 54-АВ Н o nn 7.11 (аа, У-8.97, 2.40 Hz, 1 Н) . t, 4 H), 3.68 (5, C H), (6,7-dihydro-5H-pyrroloi3,4- 2.27 (c, C H) d9 | and I carboxylic acid

M o (meob) b freq./million 8.53 (5, 1 N), "Me If; p 8.33 (4, 4-8.84 HZ, 1 NU, 7.90 (4,

M. and M - 93.54 Hz, 1 N), 7.60 (y, 9-2.27 Hz, r M 1 N), 7.42 (а, 9-2.27 Hz, 1 N), 7,12

M (aa, y-8.97, 2.40 Hz, 1 H), 6.71 (a, 5a-AS H on 923.54 Hz, 1 H), 6.53(4.9452.53gC, C (1-isopropyl-1H-pyrazol-3-yl)-amide 5-|1H), 4.46 (ai, U-13.39, 6.69 Hz, 1 (6,7-dihydro-5H-pyrrolo |3,4- H), 4,19 (a, 9U-6,82 Hz, 4 H), 1,50 (4, a|pyrimidin-4-yloxy)-indole-1- 93-6,82 Hz , 6 N) carboxylic acid

E o (mer) 56 parts/million 12.80 (Bk. 5., 1

E H E H N), 10.74 (5, 1 H), 8.55 (5, 1 H), 8.30

In SMN (a, 9-8.84 Hz, 1 N), 8.18 (a, 9-3.28

M M with HC, 1 N), 7.45 (5.1 N), 7.13 (5.1 N), 54-Ar M rya 6.72 (0.9-3.28 Hz, 1 N) , 6.67 (5, 1,470.9

N o nn H), 4.08 (a, 9-1.52 Hz, 2 H), 4.06 -

I5-(1-trifluoromethyl-cyclopropyl)-1 H- 4.13 (t, 2 NU), 1.40 (Bg. 5., 2 H), 1.50 pyrazole-Z-iliamide 5-(6,7 -dihydro-BN-|(7.5.2H).pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid

Example 55 55-А. Tert-butyl ether 4-(11-(5-trifluoromethylpyridin-3-ylcarbamoyl)-1H-indol-5-yloxy)|-5,8- dihydro-6bH-pyrido|3,4-4Y|pyrimidine-7-carbon acid still EC in x cho

M. 22 M M r d-

M (in) N

J

A solution of tert-butyl ether 4-(1H-indol-5-yloxy)-5,8-dihydro-6H-pyridoyl3,4-4|pyrimidine-7-

carboxylic acid (92 mg, 0.25 mmol) and THF (5 mL) was treated with Mann (20 mg, 0.50 mmol, 60 95 in mineral oil) and then the compound of Example 13-A (304 mg, 0, 75 mmol).

After 24 hours the reaction mixture is concentrated in vacuo and partitioned between DCM and water.

The organic layer is separated, dried and concentrated. The crude residue is purified using

KFC (5-90 95 EOAc/heptane) and get the desired compound. MS (IER) t/2 555.1 (M-n1). 55-8. (5-Trifluoromethylpyridin-3-yl)-amide 5-(5,6,7,8-tetrahydropyridoi|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

E.S

Mao x z o -

M. 22 M M r d-

M (in) N

N

Tert-butyl ether solution 4-(11-(5-trifluoromethylpyridin-3-ylcarbamoyl)-1H-indol-5-yloxy|-5,8- dihydro-6bH-pyrido/3,4-4|pyrimidine-7- carboxylic acid (47 mg, 85 μmol), DCM (2 ml) and TFC (2 ml) are stirred at RT for 2 h. Then the solution is concentrated and the residue is purified by semi-preparative HPLC (C18; 10-100 965 ACN/NgO with the addition of 0.1 95 MNAOH) and obtain the desired compound. MS (IR) t/2 455.1 (M--1); "H NMR (400 MHz, DMSO-dv) b freq./million 10.54 (5, 1 H), 9.11 (a, y-2.3 Hz, 1 H), 8.72 (5, 1 H), 8.50 (I, Y-2.0 Gu, 1 H), 8, 40 (5, 1 H), 8.30 (y, 9U-8.8 Hz, 1 H), 8.11 (a, 9U-3.8 Gu, 1 H), 7.46 (9, 9- 2.3 Hz, 1 H), 7.13 (aa, 9U-9.0, 2.4 Hz, 1 H), 6.81 (y, 9U-3.5 Gu, 1 H), 3.82 (5.2 N), 3.04 (Her, y-5.8 Hz, 2 N), 2.73 (I, 9-5.6 Hz, 2 N).

The following compounds are obtained by a similar method. 55-60. (5-Trifluoromethylpyridin-3-yl)-amide (g)-5-(b-methyl-5,6,7,8-tetrahydropyrido|3,4-4|pyrimidin-4-yloxy)-indole-1-carbon acid

E.S

Mo x y (y Ak

M. U. -UM

M (in) N

N

MS (IER) t/2 469.0 (M--1); "H NMR (400 MHz, meob) b frequency/million 9.07 (y, 9U-2.3 Hz, 1 N), 8.64 (5.1 N), 8.57 (5.1 N) , 8.32 - 8.42 (t, 2 N), 7.95 (9, 9-3.5 Hz, 1 N), 7.41 (а, 9О-2.5 Hz, 1 N), 7 ,12 (aa, 2-91, 2.3 Hz, 1

H), 6.77 (a, U-3.8 Hz, 1 H), 4.05 (a, U-7.6 Hz, 2 H), 3.18 (daa, U-10.5, 6 ,3, 4.2 Hu, 1 H), 3.04 (aa, U-17.4, 3.8

Hu, 1 H), 2.52 (ai, 9-17.4, 10.4 Hz, 1 H), 1.37 (a, 9-6.3 Hu, Z H).

Example 56 56-А. Tert-butyl ether 4-(1-(5-tert-butylisoxazol-3Z-ylcarbamoyl)-1H-indol-5-yloxy)|-5,8- dihydro-6bH-pyrido|3,4-d|pyrimidine-7 -carboxylic acid. g and; Kh

M. M 6

M"

M o n n a Her

To a solution of 4-(1H-indol-5-yloxy)-5,8-dihydro-6H-pyrido|3,4-4|pyrimidine-7-carboxylic acid tert-butyl ether, the compound of example 31-C (1.1 g, 3.00 mmol) in THF (50 ml), Man (0.360 g, 9.01 mmol) was added under a nitrogen atmosphere at 0"C, and the resulting mixture was stirred for 1 h. Then a solution of phenyl ether (5-tert- of butylisoxazole-3-yl-carbamic acid (1.56 g, 6.00 mmol) in THF. The resulting mixture was stirred at 0 °C for 1 h. The mixture was allowed to warm to RT and stirred overnight. The reaction was then quenched with a saturated aqueous solution of chloride ammonium and then extracted with EtOAc (2x).The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent removed.

Then the residue is purified by KFC (0-70 96 EOAc/heptane) and the desired compound is obtained. MS (ER) t/2 533.1 (M--1). 56-8. (5-tert-Butylisoxazol-3-yl)-amide

1-carboxylic acid. g shi; H

M. M 6 is already M

M o nn

N

Tert-butyl ether of 4-1P1-(5-tert-butylisoxazol-3-ylcarbamoyl)-1H-indol-5-yloxy|-5,8-dihydro-6H-pyridoY3,4-d|Ipyrimidine-7-carboxylic acid (1.4 g) was stirred in a mixture of DCM (200 ml) and TFC (2 ml) overnight. After removing the solvents, the residue is neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with EIOAc (3). The combined organic layers are washed with water, brine, dried over magnesium sulfate, filtered, and the solvent is removed. Then the residue is purified using KFC (0-10 Fo, 2 M Mnz in Meon/DXM) and the desired compound is obtained. MS (IER) t/2 432.9 (M-1);

NMR NMR (400 MHz, Meor) 5 ppm 8.37 (5, 1 H), 8.33 (y, U-8.84 Hz, 1 H), 7.88 (a, 9U- 3.79 Hz, 1 N), 7.38 (0.9-2.02 Hz, 1 N), 7.10 (aa, 9-8.84, 2.27 Hz, 1 N), 6.72 (a, U-3.79 Hz, 1 N), 6.65 (5, 1 N), 3.94 (5.2

H), 3.17 (I, U-5.94 Hz, 2 H), 2.87 (I, 9U-5.68 Hz, 2 H), 1.38 (5, 9 H).

The following compounds are obtained by a similar method. 7 styuzhanyanniye | nyaieyoutmo era

IS

SS.

M B M i |c) (meob) b frequency/million 8.35 (B. 5., 1 H), r M 7.48 (a, 9U-8.84 Hz, 1 H), 7.04 (I, 9-6,69

Hu, 1 H), 6.66 (5, 1 H), 6.49 (bBg. 5., 1 H), 56-C and on 3.93 (rg 5.2 H), 3y5 (0g 85.2), 4 -fluoro-2-methyl-(5-tertiary 5., 2 H), 2.58 (B. 5., C H), 1.38 (5.95 butylisoxazol-3-yl)-amide 5- (5,6,7,8-|.7 tetrahydro-pyridoY3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid. pf x M (meOb) b freq./million 8.35 - 8.39 (t, 2

Mo M | o H), 7.90 (a, 9-3.79 Hz, 1 H), 7.38 (a, 5Bv-0 r 9-2.27 Hz, 1 H), 7.09 (5, 1 H ), 6.71 (a, 433.0

M o nn 9U-3.79 Hz, 1 N), 6.37 (5.1 N), 4.00 (5.2 "

H H), 3.21-3.25 (t, 2 H), 2.91 (5.2 H), (b-trifluoromethyloxazol-g-yl)-amide | 1.36 (5.9 N). 5-(6,7-dihydro-5H-pyrroloic|3,4-9|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid.

М. ,8 Hz, 1

M. M o H), 7.39 (0, U-2.3 Hz, 1 H), 7.10 (aa, ra M 3-9.0, 2.4 Hz, 1 H), 6.73 (y, 9U-3.8 Hz, 1 56-E M about them H), 6.65 (5, 1 H), 3.90-4.08 (t, 2 H), 4471

H 3.05-3.16 (t, 1 H), 3.00 (aa, 9-171, (b-tert-butylisoxazol-3-yl)-amide tv 39: vnz through D and ()-5- (6-methyl-5,6,7,8-tetrahydro-H she ' she ' Hz, pyridoyiZ3,4-4|pyrimidin-4-yloxy)-). indole-1-carboxylic acid

(DMSO-dv) 6 ppm 8.40 (5.1 N),

Ma o X 8.29 (a, 9U-9.09 Hz, 1 H), 8.15 (a, 9-3.28 (th hundred Hz, 1 H), 7.43 (y, 9-1, 26 Hz, 1 N), 7.11

M M zdi (aa, y-8.72, 1.39 Hz, 1 H), 6.75 (a, .,, p 93.03 Hz, 1 H), 6.68 (5, 1 H), 3.79 - 56-E MO o nn 3.98 (t, 2 H), 2.91 - 3.05 (t, 1 H), 2.85 4472

H (a, 9-16.17 Hz, 1 H), 2.34 (ad, dU-16.17, (bB-tert-butylisoxazol-3-yl)-amide 19.60 Hz, 1 H), 1 .34 (5.9 H), 1.21 (a, (-)-5-(5)-6-methyl-5,6,7,8-9U-6.32 Hz, 3 H). tetrahydro-pyridoY3,4-a4|pyrimidine-| IN; 8.92 minutes. (column SpigaIrac IA-4-yloxy)-indole-1-carboxylic acid mMesm/EuHn 4:6). (DMSO-dv) 6 ppm 8.40 (5.1 N),

М. ,27 Hz, 1 N), 7/1

M. Z M Sh o (aa, y-8.97, 2.40 Hz, 1 N), 6.75 (a, ra M 93.79 Hz, 1 N), 6.68 (5, 1 N) , 3.81 - 56th M about them 3.95 (t, 2 H), 2.90 - 3.02 (t, 1 H), 2.85 4471

H (aa, 9U-17.05, 3.66 Hz, 1 H), 2.34 (da, (5-tert-butylisoxazol-3-yl)-amide (- Thozo 3. "34 (5, 9 H), (NI γ-methyl-5,6,7,γ-tetrahydro- | d, 44.77 waves (SpigaIrak column IA- pyrido|3,4-4|Ipyrimidin-4-yloxy)- M SMEUN 46 r of indole-1-carboxylic acid. o 6)

IS

(6)

SS then (DMSO-dv) 6 ppm 8.41 (5.1 N),

M M 3 8.18 (a, 9-3.8 Hz, 1 N), 8.12 (y, 9-91

BA r Hz, 1 NU, 7.21 - 7.32 (t, 1 H), 6.687 (a, 4511

M o nn 93.8 Hz, 1 N), 6.67 (5, 1 N), 3.85 (5.2 "

Н H), 3.06 (Yi, Y-5.8 Hz, 2 H), 2.76 (y, 9-5.7 4-fluoro-(5-tert-butyl-isoxazole-3-|Hz, 2 H), 1,34 (5, 9 H).yl)-amide of 5-(5,6,7,8-tetrahydropyridoyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid . "more (DMSO-dv) 6 ppm 8.40 (5.1 N),

TY - x 8.29 (a, 9-91 Hz, 1 N), 8.15 (a, 2-3.5

M. Zh M y (o; Hz, 1 H), 7.43 (a, 9-2.5 Hz, 1 H), 7.11

Hm no (aa, 9U-9.0, 2.4 Hz, 1 H), 6.75 (y, 9U-3.5

Hz, 1 H), 6.69 (a, 9U-0.8 Hz, 1 H), 3.79 - 56 M o n 3.96 (t, 2 H), 3.04-Z18(t,1 H), 2.901... , also , , - 3.03 (t, 1 H), 2.85 (ad, 9-16.8, 3,4 (5-isopropylisoxazol-3-yl)-amide (5 )- Hu, 1 H), 2.33 (aa, U16.7, 10.4 Hz, 1 5-(β-methyl-o,6,7,8- sho H), 1.29 (a, 9 -6.8 Hz, 6 NU, 1.21 (a, tetrahydropyridoyiZ,4-4|pyrimidine-4- -6.3 Hz, Z H). yloxy)-indole-1-carboxylic acid. o (DMSO-dv ) 6 parts/million 8.40 (5, 1 N), he X 8.28 (a, 9-91 Hz, 1 N), 8.14 (a, 2-3.5 oo HC, 1 N) , 7.42 (a, 9-2.3 Hz, 1 N), 7.11

M M z (aa, 9U-8.8, 2.3 Hz, 1 H), 6.74 (a, 9U-3.8

Bv-/ re Gu, 1 H), 6.65 (5, 1 H), 3.80 - 3.95 (t,2 48310

M o nn H), 2.90 - 3.03 (t, 1 H), 2.84 (d9, '

H y-16.9, 3.5 Hz, 1 H), 2.33 (α, 9-16.7, (5-cyclopropylisoxazol-3-yl)-amide | 10.4 Hz, 1 H), 2 ,12-2,21 (t, 1 H), 1,21 (t)-5-(6-methyl-5,6,7,8-tetrahydro-|(y, 9-61 Hz, 3 H), 1.03-1.12 (t, 2 H), pyridoyi3,4-4|pyrimidin-4-yloxy) - 0.91 -0.97 (t, 2 H). indole-1-carboxylic acid.

(DMSO-dv) 6 ppm 8.40 (5.1 N),

M. 8; x 8.29 (y, 9-8.8 Hz, 1 H), 8.16 (a, 9-38 and IF; du Hz, 1 H), 7.43 (a, 9-2.5 Hz, 1 N), 7.11 o M - (ad, U-8.8, 2.3 Hz, 1 N), 6.72 - 6.78 (t, 2 N), 3.81 - 3.95 ( t, 2 N), 3.64 - 3.76 z6'K m o (t, 1 N), 2.90-3.03 (t, 1 N), 2.85 (49,..0009Й

H U-16.5, 3.4 Hz, 1 H), 2.31 - 2.41 (t, C (B-cyclobutylisoxazol-3-yl)-amide |H), 2.18 - 2.31 ( t, 2 H), 1.98-2.12 (t, (3)-5-(6b-methyl-5,6,7,8-tetrahydro- (t, 1 H), 1.18 - 1.24 pyridoi|3,4-4|pyrimidin-4-yloxy)- | (t, Z H). indole-1-carboxylic acid. more (DMSO-dv) 6 ppm 8.39 (5, 1 N), ie - x 8.30 (a, U-8.8 Hz, 1 N), 8.15 (a, 9-38

S ke Gu, 1 H), 7.43 (a, 9-2.5 Hz, 1 H), 7.11

HU M (ad, 9U-9.0, 2.4 Hz, 1 N), 6.71 - 6.78 (t, 56-Y M 2 N), 3.82 (5, 2 N), 3, 63 - 3.75 (t, 1 H), 431.3 of them o n 3.03 (I, 9-5.8 Hz, 2 H), 2.72 (, 9-5.7 Gu,

II I 2 H), 2.30 - 2.43 (t, 2 H), 2.17 - 2.31 (5-cyclobutylisoxazol-3-yl)-amide (t, 2 H), 1.99- 2.11 (t, 1 H), 1.86 - 5-(5,6,7,8-tetrahydropyridoi|Z,4- 1.99 (t, 1 H). 9|Ipyrimidin-4-yloxy)- indole-1-carboxylic acid. H (DMSO-dv) 6 ppm 8.39 (5, 1 N), oo 8.28 (a, U-8.8 Hz, 1 N), 8.14 (a, 9-3 ,8

We M s Hz, 1 H), 7.43 (y, 9-23 Hz, 1 H), 7.11 5v-M re (aa, 9U-9.0, 2.4 Hz, 1 H), 6 .74 (y, 9-3.5 4172

M o nn HC, 1 N), 6.65 (5, 1 N), 3.82 (5,2 N), "

H 3.03 (I, 9-5.8 Hz, 2 H), 2.72 (, 9-5.7 Hu, (5-cyclopropylisoxazol-3-yl)-amide /)2 H), 2.12 - 2.22 (t, 1 H), 1.04-1.13 5-(5,6,7,8-tetrahydropyridoi|Z,4- (t, 2 H), 0.89 - 0.98 ( t, 2 H).9|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid.

М.

M. Z M (o; 8.29 (a, U-8.8 Hz, 1 H), 8.16 (j, 9-3.5

Khm M Hz, 1 N), 7.43 (a, 9-2.3 Hz, 1 N), 7.11 (ad, 9U-9.0, 2.4 Hz, 1 N), 6.75 ( a, 9U-3.8 96-M M o n Hz, 1 N), 6.69 (4, 2-08 Hz, 1 N), 3.82 419.0 , more , , (5.2 N) . ,6 Hz, 2 H), (5,6,7,8-tetrahydro-pyridoyi3,4- 1,29 (a, U«ty Hz, 6 H). 9|Ipyrimidin-4-yloxy)-indole-1 - carboxylic acid.

M. 0 (DMSO-dv) 6 parts per million 8.40 (5.1 N), and t If; d 8.29 (a, U-8.8 Hz, 1 H), 8.15 (j, 9-3.5

M. M o 8) Hz, 1 N), 7.43 (a, 9-2.5 Hz, 1 N), 7.12 ra M (ad, 9U-9.0, 2.4 Hz, 1 N ), 6.75 (a, 9U-3.8 56-0 M o! and Gu, 1 H), 6.67 (5, 1 H), 3.82 (5.2 H), 431.2

H 3.03 (I, 9-5.8 Hz, 2 H), 2.72 (Y, 95.7 Hu, (5-(1-methylcyclopropyl)-isoxazole-9 7 097 (t dya l2g-1l18( t,2 H),

3-yl|-amide of 5-(5,6,7,8-tetrahydro- " " " and pyridoyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

o (DMSO-dv) 6 ppm 8.40 (5, 1 N), ha X 8.28 (a, U-8.8 Hz, 1 N), 8.15 (a, 9-38 so Hz, 1 N), 7.43 (y, 9U-2.3 Hz, 1 N), 7.11

M M back (ad, 9U-9.0, 2.4 Hz, 1 H), 6.75 (a, 9U-3.5 rya Gu, 1 H), 6.66 (5, 1 H), 3 .80 - 3.95 (t,2 56-R Mo nn H), 2.91 - 3.03 (t, 1 H), 2.85 (aa, 445.3

H U-16.9, 3.5 Hz, 1 H), 2.34 (yes, U-16.8,

15-(1-methylcyclopropyl)-isoxazole-| 10.2 Hz, 1 H), 1.46 (5, C H), 1.21 (a,

Z-yl|-amide (g)-5-(b-methyl-5,6,7,8-3-6.3 Hz, 3 H), 1.12-1.17 (t, 2 H), tetrahydro-pyridoY3,4-4|pyrimidine- |0.91 - 0.96 (t, 2 H). 4-yloxy)-indole-1-carboxylic acid.

IS

M o X (DMSO-dv) 6 ppm 8.42 (5, 1 N), (th hundred 8.19 (a, 9-3.79 Hz, 1 N), 8.12 (a, 9 -8.84

M M z-d Hz, 1 NU, 7.27 (a, 9-7.58 Hz, 1 H), 6.87 re (a, 9U-3.79 Hz, 1 H), 6.67 (5 , 1 H), 3.90 56-0 M o nn (a, 9U-7.07 Hz, 2 H), 3.00 (ada, 9U-10.23, 465.1

H 6.44, 3.79 Hz, 1 H), 2.86 (aa, 9U-17.18, (b-tert-butylisoxazol-3-yl)-amide 13.28 Hz, 1 H), 2, 40 (aa, 9-17,18, 10,36 (-3-4-fluoro-5-(6-methyl-5,6,7,8-Gu, 1 H), 1.34 (5, 9 H ), 1.22 (y, 9-6.32 tetrahydro-pyrido|3,4-4|pyrimidine-|Hz, З H). 4-yloxy)-indole-1-carboxylic acid.

IS

M (c) (DMSO-dv) 6 ppm 8.42 (5.1 N),

Ty 7x VH d 8.19 (a, 9U-3.79 Hz, 1 H), 8.12 (a, 9U-8.84

M. Ж M y |c) Hz, 1 NU, 7.27 (a, 9-7.58 Hz, 1 H), 6.87

X- M (a, 9U-3.79 Hz, 1 H), 6.67 (5, 1 H), 3.90 56-38 M o! them (a, 9U-7.07 Hz, 2 H), 3.00 (ada, 9U-10.23, 465.1

H 6.44, 3.79 Hz, 1 H), 2.86 (aa, (5-tert-butylisoxazol-3-yl)-amide 4- 217.18,3.28 Hz, 1 H), 2, 40 (yes, 9U-17.18, 10.36 Hz, 1 H), 1.34 (5.9 H), fluoro-5-(B)-6-methyl-5,6, 7,8- 1 ,22 (a, 2-6,32 HZ. With H) tetrahydropyrido|Z,4-4|Ipyrimidine-4-| " ' ' B, I yloxy)-indole-1-carboxylic acid

M.O (DMSO-dv) 6 ppm 8.40 (5, 1 N), tx X 8.27 (a, 9-91 Hz, 1 N), 8.15 (a, 2-3 ,8

SA ke Gu, 1 H), 7.43 (a, 9-23 Hz, 1 H), 7.11

H. M (ai, 9U-9.0, 2.4 Gu, 1 H), 6.74 (a, 9-33 5Bv-5 h, o M Gu, 1 H), 6.65 (5, 1 H), 3.79 - 3.95 (t, 2 431.2 and Н H), 2.90 - 3.01 (t, 1 H), 2.85 (909,

Also I Tu 16.9, 3.5 Hz, 1 H), 2.34 (ad, U-16,8, (5-cyclopropylisoxazol-3-yl)-amide 10.2 Hz, 1 H), 212- 223 (t, 1 H), 1.21 5-((5)-6-methyl-5,6,7,8-tetrahydro- (a, 9-6.3 Hz, C H), 1.05- 1.12 (t, 2 H), pyridoyi3,4-4|pyrimidin-4-yloxy) - 0.91 -0.97 (t, 2 H). indole-1-carboxylic acid

M (c) (DMSO-dv) 5 ppm 8.40 (5.1 N),

Tj t If; where 8.27 (a, U-8.8 Hz, 1 H), 8.15 (a, 9-38

M. 22 M no 19) Gu, 1 H), 7.43 (a, 9-24 Hz, 1 H), 7.11 re M (ai, 9U-9.0, 2.3 Hz, 1 H) .

H H), 2.91 - 3.04 (t, 1 H), 2.80 - 2.90 (t, (5-cyclopropylisoxazol-3-yl)-amide 122 -2g40 (t, 1 H), 212 -222 5-((B)-6-methyl-5,6,7,8-tetrahydro- (t, 1 Nu, T, 21 (a, 9-63 Hu, C H), 1,04 - pyrido| 3,4-a-pyrimidin-4-yloxy)- | 112 (t, 2 H), 0.90 - 0.98 (t, 2 H). indole-1-carboxylic acid

M. about SE, | (DMSO-v8) 6 ppm 8.41 (5.1 N),

C If; DAO |8.29 (y, 958.8 Hz, 1 N), 8.15 (y, 9-38

M. M 0 Hz, Well, 7.43 (y, 9-2.3 Hz, 1 N), 7.12

Hm ve (49, 9-9.0, 2.4 Hz, 1 H), 7.04 (5, 1 H), z, 6.75 (a, 9-3.5 Hu, 1 H), 3 .77 - 3.96 (t, 560 her on 2 H), 2.95 - 3.05 (t, 1 H), 2.86 (94, 49941 (5-(1-trifluoromethyl-cyclopropyl)-|U717 ,1, 3.4 Hu, 1 H), 2.32 (yes, 925.9, isoxazol-3-ylI-amide 5-((5)-6-methyl-1.9 Hz, 1 NU), 1.50 - 1.60 (t, 4 H), 1.22 5,6,7,8-tetrahydro-pyridoi3,4- (a, 3-63 Hz, C H) 9|Ipyrimidin-4-yloxy)-indol- 1- carboxylic acid m. o (DMSO-a) b parts/million 1.21 (y, 9U-6.3 "Me x Hz, Z H), 1.29 (a, U-6.8 Hz, 6 H), 2.27 -

M i mo b o 240 (t, 1 nn), 2.85 (ad, U-16.9, 3.5 Hz,

Uk s 1 H), 2.92 - 3.02 (t, 1 H), 3.05 - 3.18 - (t, 1 H), 3.80 - 3.95 (t, 2 H), 6 .69 (5, 1 96-U M o n H), 6.75 (a, U23.8 HC, 1 NU, 7.12 (49, 433.2

What is 4-9.0, 2.4 Hz, 1 H), 7.43 (4, 9-2.3 Hz, 1 (5-isopropylisoxazol-3-yl)-amide 5- H), 8.16 (a, u3.8 Hz, 1 H), 8.28 (a, (5)-b-methyl-5,6,7,8-...00 9-8.8 Hz, 1 H), 8 .40 (5.1 N) tetrahydropyridoyl 3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (DMSO-α) 6 parts/million 0.90 - 0.97 (t, "more; 2 H), 1.11-1.18 (t, 2 H), 1.21 (4, p If; i Ch-6.3 Hz, Z NU, 1.46 (5, Z H), 2, 34 (ah,

M. z M o 0 |0-16.8,10.2 Hz, 1 N), 2.85 (49, U-16.9, ra M 3.5 Hz, 1 N), 2.90 - 3 ... 38 Hz, 1 NU, 7.11 (44, 9-9.0, 2.4 Hz,

I(5-(1-methylcyclopropyl)-isoxazole- Mody Go, vv "is pd 6 Tv

Z-iliamide 5-(5)-6-methyl-B,b,7,8-8,40 (5 and in this, tetrahydropyridoZ,4-4|Ipyrimidine-4- |" " yloxy)-indole-1- carboxylic acid.

Has in; (DMSO-db) 6 ppm 8.41 (5.1 N),

Ty 7 8.27 (a, 9-91 Hu, 1 H), 8.15 (a, U-3.8

M. M 8 Hz), 743(a, 94-25 Hz, 1 H), 7/1

Bv-x MN Km (49, 4-9.0, 2.4 Hz, 1 N), 6.74 (a, 9-3.8 d17 o n Hz, 1 N), 6.65 (5, 1 H), 3.92 (5, 2 H), (B-cyclopropylisoxazol-3-yl)-amide | 2.06 (B 925.7 Hz, 2 H), 2.74 (i, U-5.7 Hu, 5-(5,6,7,8-tetrahydropyrido(4,9-2 MH), 212 - 2.22 (t, 1 H), 1.04 - 1.13 a|pyrimidin-4-yloxy)-indol-1- (t, 2 H), 0.90 - 0.98 (t, 2 H) carboxylic acid

M. o g IF; A (DMSO-dv) b parts/million 8.44 (5.1 N),

M. is M about 18.29 (a, 9-91 Hz, 1 H), 8.16 (a, 9-3.8 and HC, 1 H), 7.44 (a, 4-2.5 Hz , 1 H), 7.12 433 1 56-U MN o y (aa, U-9.0, 2.4 Hz, 1 H), 6.76 (a, U-3.8 '

Hu. 5.7 Hz, 2 H), 2.79 (5,6,7,8-tetrahydropyrido|4,3- (imaginary y, Y-5.7 Hz, 2 H), 1.34 (5.9 H ) of 9|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid

Mao Zedong and t If; where with |(DMSO-yv) b part/million 8.40 (5.1 N),

M. M o 8.30 (a, U-8.8 Hz, 1 H), 8.15 (a, 9-3.8 re M Hz, 1 H), 7.43 (a, 9-2, 3 Hz, 1 H), 7.12 (aa, 9U-9.0, 2.4 Hz, 1 H), 7.04 (5.1 H), 96-X and OH 6.75 (4, 923 .8 Hz, 1 NU, 3.84 (5, 2 H), 485.1 (5-(1-trifluoromethylcyclo-propyl)-| ... |pyrimidine-4-yloxy)-indole-1-carboxylic acid more)

That is IF; where (DMSO-iv) 6 ppm 8.40 (5.1 N),

Mi 22 M that 8) 8.30 (a, 9U-8.8 Hz, 1 H), 8.15 (a, 9-3.8 re M Hz, 1 H), 7.43 (a, 9- 2.3 Hz, 1 N), 7.12 (aa, 9U-9.0, 2.4 Hz, 1 N), 7.04 (5.1 N), 96th and on 6.75 (4 . 73 (6,955.7 Hu, isoxazol-3-ylI-amide 5-(5,6,7,8- 2 H), 1.46-1.61 (t, 4 H) tetrahydro-pyridoY3,4-4 |pyrimidin-4-yloxy)-indole-1-carboxylic acid (DMSO-iv) 6 parts per million 10.58 (5.1 N),

M. 0 8.39 (5, 1 N), 8.27 (y, 9-9.09 Hz, 1 N),

Tj t If; d 8.14 (a, 9-3.79 Hz, 1 N), 7.40 (a, 9-2.02

M. M M GHz, 1 N), 7.07 (yes, 9U-8.97, 2.40 Hz, 1 N),

X M 6.70 (a, 9-3.79 Hz, 1 N), 6.16 (5.1 N), 56-27 m» o and 3.87 (a, 9-6.32 Hz, 2 H), 3.75 - 3.82 (t, A4A

H Z H), 2.94 - 2.96 (t, 1 H), 2.82 - 2.87' (B-cyclopropyl-1-methyl-1 H - (t, 1 H) 2.33 (dyda, 9U-3.85, 1.83, 1.64 pyrazol-3-yl)-amide 5-((5)-b-methyl- | HC, 1 H), 1.85 - 1.96 (t, 1 H), 121 (9, 5,6,7,8-tetrahydro-pyridoyi3,4- -6.32 Hu, Z H) 0.92 -1.02 (t, 2 H), α|Ipyrimidine-4- yloxy)-indole-1- 0.62 - 0.70 (t, 2 H). carboxylic acid

GE

M y; E (DMSO-ав) 6 ppm 8.40 (5.1 N),

Tj, 18.29 (y, 99.09 Hz, 1 H), 8.17 (9, 9U-3.79

Mi 2 M M HC, 1 H), 7.42 (a, 9-2.27 Hz, 1 H), 7.07 re M -7.12 (t, 2 H), 6.74 (a, 9 -3.79 Hz, 1 56-AA ke o nn H), 3.95 (5, Z H), 3.87 (y, U-6.06 Hz, 2 4720

H H), 2.92 - 3.00 (t, 1 H), 2.85 (aa, ' (1-methyl-5-trifluoromethyl-1 H- U-16.93, 3.54 Hz, 1 H ), 2.33 (aa, pyrazol-3-yl)-amide 5-((5)-6-methyl- |9-16.55, 10.48 Hz, 1 H), 1.21 (a, 9 -6.06 5,6,7,8-tetrahydropyrido!|3,4-Gu, with H).9|Ipyrimidin-4-yloxy)-indole-1- carboxylic acid

Example 57 57-А. 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (5-tert-butylisoxazol-3-yl)-amide.

(in)

M. m 1 9 and re

N o nn

Tert-butyl-4-(1H-indol-5-yloxy)-5H-pyrrolo|3,4-4|pyrimidine-6(7H)-carboxylate (127 mg, 0.360 mmol) is dissolved in THF (8 ml), blown with nitrogen and cooled to 0 °C. Sodium hydride (23 mg, 0.575 mmol, 60 95 in mineral oil) was added and the mixture was stirred for 10 min. Undiluted phenyl-5-tert-butylisoxazole-3-ylcarbamate (140 mg, 0.538 mmol) was added ) and the reaction mixture is stirred at room temperature overnight. The reaction mixture is cooled in an ice bath and the reaction is quenched with saturated ammonium chloride solution (100 mL). The mixture is then diluted with ethyl acetate and the product is extracted (2x100 mL of EtOAc). The organic layers are combined, dried and concentrate to obtain a brown oil, which is dissolved in 10 mL of DCM and cooled in an ice bath and 10 mL of TFA is added. After the reaction is complete, the DCM and TFA are removed and ethyl acetate is added to the residue and ammonium hydroxide is added to neutralize the remaining TFA. The mixture is diluted with water and extracted ethyl acetate (2 x 50 ml).The organic layers are separated, dried and concentrate. The residue is absorbed on silicon dioxide and purified by KFC (0-6 95 methanol/DHM) and obtain

M-(b-tert-butylisoxazol-3-yl)-5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-1H-indole-1-carboxamide. MS (IER) t/2 419.2 (M--1); "H NMR (400 MHz, DMSO-av) b frequency/million 8.56 (5, 1 H), 8.29 (y, 3-8.84 Hz, 1 H), 8.17 (a, 9 -3.79 Hz, 1 H), 7.47 (y, 9-2.27 Gu, 1 H), 7.15 (ad, 9U-8.97, 2.40 Hz, 1 H), 6, 76 (a, 93.28 Hu, 1 H), 6.68 (5.1 H), 4.07 - 4.14 (t, 4 H) 1.34 (5, 9 H).

The following compounds are obtained by a similar method. with. and MS (ER)

OT seyuuennnyanyuy | 00 not equal to 1

M o, (DMSO-av) 6 parts/million 8.61 (5.1 N), and If; X 8.42 (a, 9U-9.09 Hz, 1 H), 8.11 (a,

Mo 2 M | M 9-3.79 Hz, 1 H), 7.44 (a, 9-2.27 Hz, 1 57-V rya o, NU, 7.11 (ad, U-9.22, 2.40 Hz , 1 H), 419.9 and o nn 6.67 (a, 9-3.54 Hz, 1 H), 6.22 (5.1 , , , H), 425 (Brg. 5., 4 H ) 1.28 (5.9 N). -carboxylic acid

Gee)

CO. where (meOb) 5 parts/million 8.52 (5.1 N),

СХ МХ 7.70 (a, 9-8.84 Hz, 1 H), 7.29 (a, 9-2.27 Hz, 1 H), 7.02 (da, 9U-8.84, 57 - with M o 227 Hz, 1H), 665(5.1 ), 644(5.11 7332 , , , H), 4.19 (a, 9U-5.56 Hz, 2 H), 4.18 ( 5, (b-tert-butylisoxazol-3-yl)-amide 5-2H), 2.60 (in, 3H), 1.39 (in, 9H). (6,7-dihydro-5H-pyrroloic|3,4-9|Ipyrimidin-4-yloxy)-2-methylindole-1-carboxylic acid. o (DMSO-av) 6 ppm 8.58 (5, 1 N), ha X 8.35 (a, 9U-9.09 Hz, 1 N), 8.19 (a, o 3-3 .54 Hz, 1 N), 8.01 (a, 9U-7.83 Hz, 1

M M di H), 7.72-7.75 (t, 1 H), 7.68 (ad, 57-00 M rya 3-6.82, 1.26 Hz, 1 H), 7.50 ( a, 9-2.27 413.1

N o nn Hz, 1 H), 7.39 (her, U-7.58 Hz, 1 H), 1,2-benzisoxazol-Z3-ylamide 5-(6,7- 7.16 (99, 5-8, 97, 2.40 Hz, 1 NU, 6.79 dihydro-5H-pyrroloyi3,4-4|pyrimidine-4- (a, 93.79 Hz, 1 H), 4.12 (9, 9-14.91 yloxy)-indole-1-carboxylic acid. Hz, 4 N).

IS

(DMSO-dv) 6 parts per million 8.68 (5, 1 N), o 8.58 (y, U-8.84 Hz, 1 N), 8.13 (a, ha X 3-3, 54 Hz, 1 N), 7.68 (aa, 9U-8.84,

M 5.56 Hz, 2 H), 7.42 (a, 9-2.53 Hz, 1 57-E | MA M | o H), 7.32 (ad, U-8.84, 4.55 Hz, 2 N), 4571

Measure 7.08 (ai, 9U-8.97, 2.40 Hz, 1 H), 6.60

H o nn (a, 9U-3.54 Hz, 1 H), 6.58 (5.1 H), (3-(4-fluorophenyl)-isoxazole-5-ylamide 7538 (9, 955.31 Hz, 4 H). 5-(6,7-dihydro-5H-pyrrolo|3,4-9|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid. (DMSO-dv) 6 parts/million 8.68 (5, 1 H), o) 8.58 (a, 9U-9.35 Hz, 1 H), 8.13 (a, y t If; X 3-3.54 Hz, 1 H), 7, 83 (a, U-8.08 Hz, 2

Was | A M u H), 7.42 - 7.52 (t, 5 H), 7.09 (yes, 439 1 rya (6) 3-8.97, 1.89 Hz, 1 H), 6.61 (a, 9U-3.54 " ich o nn Hz, 1 H), 6.59 (5, 1 H), 4.36 (y, 3-3.54 Hz, 4 H). (Z-phenylisoxazole- 5-yl)-amide of 5-(6,7-dihydro-5H-pyrroloi|3,4-d|pyrimidin-4-yloxy)-indole-1-carboxylic acid. o (DMSO-dv) 6 parts/million 8.62 (5, 1 N), ha X 8.44 (a, 9U-8.84 Hz, 1 N), 8.11 (a,

M y-3.54 Hz, 1 H), 7.44 (a, 9-2.53 Hz, 1

Ma M | o NU, 7.11 (ad, 2-9.09, 2.53 Hz, 1 H), 57th Mrya 6.67 (y, 9-3.54 Hz, 1 H), 6.17 ( 5.1 405.1

N o nn NI, 4.26 (a, 9U-5.56 Hz, 4 H), 2.88 - (Z-isopropylisoxazol-5-yl)-amide 5-(6,7- | 296 (t, 1 H), 1.23 (y, Y-6.82 Hz, 6 dihydro-5H-pyrrolo|3,4-d|pyrimidine-4-H).yloxy)-indole-1-carboxylic acid. (DMSO-dv) 6 ppm 8.62 (5, 1 N), 8.43 (a, 9U-8.84 Hz, 1 N), 8.11 (a,

Mat o X uU-3.79 Hz, 1 H), 7.43 (a, 9-2.27 Hz, 1 and r ! zm H), 7.10 (ad, U-8.84, 2.53 Hz, 1 N),

M , 6.66 (y, U-4.04 Hz, 1 N), 6.11 (5.1 zn and Mom 79 N), 4.25 (bg. 8., C H), 4.08 ( Bk. 8. 1 419.0

H o nn H), 2.41 - 2.45 (t, 2 H), 1.96 (da, (3-isobutylisoxazol-5-yl)-amide 5-(6,7- pu 1 Nu, 0, 94 (y, dihydro-5H-pyrrolo|3,4-d|pyrimidine-4-'' I yloxy)-indole-1-carboxylic acid.

Ma and; (MeOb) 5 parts/million 8.54 (5, 1 N), (y Z 8.39 (a, 9U-9.09 Hz, 1 N), 7.93 (a,

M. mo 923.79 Hz, 1 H), 7.44 (a, 9-2.27 Hz, 1 57-I| M re o NI, 7.15 (ad, U-8.97, 2.40 Hz, 1 N), 433.1

N o nn 6.75 (9, 9-3.79 Hz, 1 N), 6.32 (5, 1

3-(2,2-dimethylpropyl)-isoxazol-5-yl|- av m 5 n) 2.56 (in, 2 H), amide 5-(6,7-dihydro-5H-pyrroloi|3,4- ' ' ' And 9|Ipyrimidin-4-yloxy)-indole-1- carboxylic acid.

(DMSO-dv) 6 parts per million 8.62 (5, 1 N), more) 8.42 (a, U-8.84 Hz, 1 N), 8.10 (a, y t If; X 93.79 Hz, 1 N), 7.43 (y, 9-2.27 Hz, 1

M. and M | /x NU, 7.11 (da, y-8.97, 2.40 Hz, 1 H), 57-3 ra (c) 6.67 (y, 9-3.79 Hz, 1 H), 6 .14 (5.1 445.0

Oh! their H), 4.22 - 4.29 (t, 4 H), 2.63 (5.1

H H), 1.89 (y, 9-12.13 Hz, 2 H), 1.73 - (Z-cyclohexylisoxazol-o-yl)-amide 5- 1.79 (t, 2 H), 1, 23 - 1.50 (t, 6 N). (6,7-dihydro-5H-pyrrolo|3,4-9|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid.

M., O se IF; is (DMSO-vol) b parts/million 8.58 (5.1 N),

M. M | b 8.51 (a, U-8.08 Hz, 1 H), 8.06 (a, 93.54 Hz, 1 H), 7.37 (y, 9y-2.78 Hz, 1

Zk M byv H), 7.04 (4.90 Hz, Nu vv, o. 1 H), 5.86 (5, 1 H), 4.15 (5, 4 H) 1.37 (Z-( 1-methylcyclopropyl)-isoxazol-o- (v, C H), 0.92 (t, 2 H), 0.77 (t, 2 H). yl|-amide 5-(6,7-dihydro-5H -pyrroloi3,4- 9|Ipyrimidin-4-yloxy)-indole-1- carboxylic acid. m. 0 (soil with TFA) (DMSO-a) b

Y o x in parts/million 8.68 (5.1 N), 8.37 (y,

M. Zh M | M 99.09 Hz, 1 N), 8.12 (y, U-3.79 Gu, 1

M o H), 7.48 (y, 90-2.27 Hz, 1 H), 7.15 (a, 57-I M M y-8.84 Hz, 1 H), 6.74 (y, 9U-3.54 Hz, 1403.1 n on H), 6.03 (5.1 H), 4.42 (a, 9-10.11 Hz, (3-cyclopropylisoxazol-5-yl)-amide 5- |4 H), 1.96 (t, 1 H), 0.97 -1.03 (t,2 (6,7-dihydro-5H-pyrroloi|3,4- H), 0.77 - 0.80 (t, 2 H). 9|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid.

M. 0 (DMSO-dv) 6 ppm 8.62 (5, 1 N), "Me If; | 8.45 (a, U-8.84 Hz, 1 N), 8.11 (4 ,

M. and M | M 93.79 Hz, 1 H), 7.43 (j, 9-2.27 Hz, 1 (c) NU, 7.11 (a, 2-8.84 Hz, 1 H), 6.66 ( and,

ZM M oh 923.79 HZ, 1 H), 6.19 (5, 1 H), 4.26 172

H (y, 951.77 Hz, 4 H), 2.24 - 2.34 (t, 4 (Z-cyclobutylisoxazol-5-yl)-amide 5- | H), 1.82-2.08 (t , Z H). (6,7-dihydro-5H-pyrrolo|3,4-9|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid. (DMSO-dv) 6 parts per million 8.56 (5, 1 N), more) 8.30 (5, 1 N), 8.17 (y, 9-3.79 Hz, 1

That is IF; db NU, 7.47 (y, 0-52.27 Hz, 1 N), 7.15 (yes,

M. and M 8) 98.84, 2.53 Hz, 1 N), 6.76 (y, 9U-3.79 57-M r M Hz, 1 N), 6.72 (5.1 N) , 4.07 -413 4191

Oh! and (t, 4 N), 2.68 (a, U-6.82 Hz, 2 N),

H 2.01-2.03 (t, 1 H), 0.95 (a, -6.82 (5-isobutylisoxazol-3-yl)-amide 5-(6,7- | Hz, 6 H). dihydro-5H-pyrrolo|3,4-d|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

M. 0 (DMSO-dv) 6 ppm 8.56 (5.1 N),

ХХ IF; where 8.29 (a, 9U-9.09 Hz, 1 N), 8.17 (a,

M. 2 M 8) 9-3.79 Hz, 1 H), 7.47 (a, 9-2.27 Hz, 1

M NI, 7.15 (ad, U-8.97, 2.40 Hz, 1 H), 57-0 M och 6.76 (a, 9-3.79 Hz, 1 H), 6.72 ( 5, 1 4334

H H), 4.06 - 4.30 (t, 4 H), 2.69 (5.2 (5-(2,2-dimethylpropyl)-isoxazol-3-yl1-H), 0.98 (5 , 9 H). amide of 5-(6,7-dihydro-5H-pyrrolo|3,4-9|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid. (DMSO-dv) 6 parts/million 8 .56 (5.1 N),

M., O 8.30 (5, 1 N), 8.16 (a, 9U-3.54 Hz, 1

Tj t If; d NU, 7.47 (a, 9-2.53 Hz, 1 H), 7.15 (aa,

M. 22 M that o 3-8.97, 2.40 Hz, 1 N), 6.76 (a, 9U-3.79 57-Р r M Hz, 1 N), 6.67 (5.1 H), 4.07 -413 445.0 y o y (t, 4 H) 2.83 (y, 9-3.54 Hz, 1 H), 1.99 (bBg. 5., 2 H) 1 .76 (a, 9U-16.17 Hz, (5-cyclohexylisoxazol-3-yl)-amide 5-|2 H), 1.34 - 1.51 (t, 6 H). (6,7-dihydro-5H-pyrrolo|3,4-9|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid. what; (DMSO-dv) 6 ppm 8.56 (5.1 N),

ХХ IF; where 8.29 (a, 9U-8.84 Hz, 1 H), 8.17 (y,

M. and M |8) 9-3.79 Hz, 1H), 7.47 (a, 9-2.27 Hz, 1

M NI, 7.15 (ad, U-8.97, 2.40 Hz, 1 H), 57 M o 6.76 (a, 9-3.79 Hz, 1 H), 6.69 (5, 1 405y

H H), 4.00 - 4.20 (t, 4 H), 3.11 (t, 1 (5-isopropylisoxazol-3-yl)-amide 5-(6,7- | H), 1.29 (a, 9U-7.07 Hz, 6 H).dihydro-5H-pyrrolo|3,4-d|pyrimidin-4-yloxy)-indole-1-carboxylic acid. o (DMSO-dv) 6 ppm 8.56 (5.1 N),

Ma X 8.30 (a, 9U-8.84 Hz, 1 H), 8.17 (a, (and If; so y-3.54 Hz, 1 H), 7.47 (a, 9-2 ,53 Hz, 1

M M di NI, 7.15 (ad, U-8.97, 2.40 Hz, 1 H), 57-88 M rya 6.72 -6.82 (t, 2 H), 4.00 -4.20 (vol. 4171

H o nn 4 H), 3.70 (t, 1 H), 2.32-2.43 (t, 2 (5-cyclobutylisoxazol-3-yl)-amide 5-H)2he,17 2.31 ( t, 2 H), 1.85 - 2.14 (6,7-dihydro-5H-pyrrolo|3,4- (t, 2 H). 9|Ipyrimidin-4-yloxy)-indole-1- carboxylic acid .

M. 0 (DMSO-dv) 6 ppm 8.55 (5.1 N),

Ty - xx 8.29 (y, 9U-9.09 Hz, 1 H), 8.16 (a,

M. z M y (o; uU-3.79 Hz, 1 H), 7.46 (a, 9-2.27 Hz, 1 r M H), 7.14 (ad, 2-8.97, 2.40 Hz, 1 N), 57-5 M M 6.75 (y, 9-3.28 Hz, 1 N), 6.65 (5, 1 403.1 n o n N), 4.04 -416(t, 4 H), 2.07-2.26 (5-cyclopropylisoxazol-3-yl)-amide 5- | (t, 1 H), 1.01-1.15 (t, 2 H), 0.87 - (6,7-dihydro-5H-pyrrolo|3,4- 0.98 (t, 2 H). 9|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid.

"still (DMSO-dv) 6 ppm 8.56 (5, 1 N), and where xx 8.29 (a, U-8.84 Hz, 1 N), 8.16 (a,

M. is M ke 93.79 Hz, 1 H), 7.47 (y, 9-2.53 Gu, 1 zm H), 7.15 (da, 2-8.97, 2.40 Hz, 1 H), 57-T M Khm 6.76 (y, 9-3.28 Hz, 1 H), 6.67 (5, 1 4171

H o n H), 4.01 - 4.19 (t, 4 Naya1 M-H), 1.46 (5-(1-methylcyclopropyl)-isoxazole-3- | (5, C H), 1.07 -1.21 (t, 2 H), 0.86 - yl|-amide 5-(6,7-dihydro-5H-pyrrolo|3,4- 1.02 (t, 2 H). 9|Ipyrimidine- 4-yloxy)-indole-1-carboxylic acid. (c) (DMSO-dv) 6 ppm 8.56 (5.1 H), m./o 8.29 (a, U-8.84 Hz, 1 N), 8.17 (a,

Ye de XX 93.79 Hz, 1 N), 7.47 (y, 9-2.27 Hz, 1 c r If; ke NU, 7.15 (da, uU-8.97, 2.40 Hz, 1 H), 5T-u MM M 6.73 - 6.78 (t, 2 H), 4.06 - 413 (t, 4471

M X-m 4 H), 3.89 - 3.94 (t, 2 H), 3.43 - "

H o n 3.A5 (t, 1 H), 3.09 - 3.18 (t, 2 H), (5-(tetrahydropyran-4-yl)-isoxazol-3- | 1.90 - 1.96 (t, 2 H), 1.64 - 1.75 (t, yl|I-amide 5-(6,7-dihydro-5H-pyrrolo|3,4-. |2 H). 9|Ipyrimidine-4 -yloxy)-indole-1-carboxylic acid. (c) (DMSO-dv) 6 ppm 8.56 (5.1 N), o 8.29 (a, 9U-9.09 Hz, 1 N ), 8.17 (a,

E XX 93.79 Hz, 1 N), 7.47 (y, 9-2.27 Hz, 1 c ro ke N), 6.78 (5, 1 N), 6.76 (t, 2 N) , 4.08 57-M M si (a, 9-2.02 Hz, 2 H), 4.07 -414 (t, 2 4611

M X-m H), 3.71 - 3.77 (t, 2 H), 3.42 - 3.49 "

N o n (t, 2 N), 2.06 (y, 9U-5.56 Hz, 1 N),

15-(4-methyltetrahydropyran-4-yl)-2.06 (α, uU-18.19, 3.54 Gu, 1 H), 1.64 isoxazol-3-yl1-amide 5-(6,7- dihydro-5H-|7 1.72 (t, 2 H), 1.95 (5, C H).pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid. (DMSO-dv) 6 parts/million 8.56 (5, 1 N), more) 8.21 (a, 9U-3.54 Hz, 1 N), 7.94 (a, y t If; d 93.79 Hz, 1 N), 7.95 (a, U-8.08 Hz, 1

Boom | M - M o H), 7.56 (y, 9-5.56 Hz, 2 H), 7.55 (5, 439 1 re M 2 H), 7.45 (5, 2 H), 7, 48 (y, 9U-2.53 " y o nn Hz, 1 H), 6.78 (5, 1 H), 4.08 (y, 9-1.77 Hz, 4 H). (5-phenylisoxazole -3-yl)-amide of 5-(6,7-dihydro-5H-pyrroloi|3,4-d|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

IS

(DMSO-dv) 6 ppm 8.55 (5.1 N),

M., O 8.30 (5, 1 N), 8.20 (y, 9-3.54 Hz, 1

And If; dl H), 7.92 (t, 2 H), 7.52 (t, 2 H), 7.44 57-X IM 2 M Io; (a, 9-2.53 Hz, 2 N), 7.42 (5.2 N), 4571

M 7.12 (t, 1 H), 6.73 (in, 1 H), 4.07 (t,

M and M 4 H).

N N

5-(4-fluorophenyl)-isoxazol-3-yl|-amide 5-(6,7-dihydro-5H-pyrrolo|3,4- a|pyrimidin-4-yloxy)-indole-1-

000111 Fkarbonovotkislotii.id///7/Ї1111111111111111111111111111ЇСsСсС more) vav;

In (DMSO-dv) 6 ppm 8.56 (5.1 N),

M. M Se 8.30 (5, 1 N), 8.17 (a, 423.79 Hz, 1 57th Mrya M R), 7.47 (a, 9-2.02 Hz, 1 N ), 1T.15 (aa, 83371

N o nn 98.97, 2.40 Hz, 1 H), 6.76 (y, 9U-3,79 (5-methylisoxazol-3-yl)-amide 5-(6,7- (t i c 4 Te and ts 4.09 - 413 dihydro-5H-pyrroloi|3,4-d|pyrimidine-4-'so' and yloxy)-indole-1-carboxylic acid.

E rava; pe ВХ - ! dl (DMSO-av) 6 ppm 8.56 (5.1 N),

СХ М Х 8.20 (a, 9U-3.79 Hz, 1 H), 8.12 (a, y-9.09 Hz, 1 H), 7.31 (aa, 9-7.83 Hz,

ZE M ohm 9.09 Hz, 1 N), 6.89 (a, 423.79 Hz, 1..7522 (MU1)

I I I H), 6.67 (5.1 H), 423 (5.2 H), 410 - (b-tert-butylisoxazol-3-yl)-amide 5- 412 (t, 2 H), 1 ,34 (in, 9 N). (6,7-dihydro-5H-pyrrolo|3,4-9|Ipyrimidin-4-yloxy)-4E-indole-1-carboxylic acid.

E ge shchi HEE E (DMSO-dv) 6 ppm 8.62 (5.1 N),

M ro M ke 8.30 (a, 9-91 Hz, 1 N), 8.18 (a, 9-3.8

TI Hz, 1 H), 7.49 (y, 9-23 Hz, 1 H), 7.17 57-AA M Hm (aa, 9U-9.0, 2.4 Hz, 1 H), 6, 81 (5.1 N), 487.0

Hn o nn 6.78 (y, 9-3.8 HC, 1 H), 4.31 (5.2 H), (5-(3,3,3-trifluoro-1,1-dimethylpropyl)- 4 .27 (5.2 H), 2.71 -2.91 (t, 2 H), isoxazol-3-ylI-amide 5-(6,7-dihydro-5H- | 1.46 (5.6 H ).pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid

SEZ

M.O (DMSO-dv) 6 ppm 8.56 (5.1 N), and 7 IF; du 8.30 (a, 9U-8.84 Hz, 1 H), 8.16 (j,

M. 22 M no iv) y-3.54 Hz, 1 H), 7.47 (a, 9-2.27 Hz, 1 rya M H), 7.15-7.16 (t, 1 H) . (a, 9-3.28 Hz, 1 N), 4.06 - 4.18 (t, 2

I5-(1-trifluoromethyl-cyclopropyl)-H), 411 (t, 2 H), 1.53 -1.60 (t, A isoxazol-3-yl|-amide 5-(6,7-dihydro-5H - n).pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (DMSO-dv) 6 parts/million 10.60 (i,

M i); X 91.01 Hz, 1 H), 8.64 (5, 1 H), 8.29 and If; to. (a, 9-8.84 Hz, 1 N), 8.16 (a, 9-3.54

СХ M - Hz, 1 H), 7.46 (y, 9U-2.53 Hz, 1 H), 7.13 (ad, 9-9.09, 2.53 Hz, 1 H), 6.72 57-AS M obi (4, 4-3.54 Hz, 1 N), 616 (5.18), 4.591..716y. . (Bg. 5., 4 H), 3.79 (in, C H), 1.91 (5, 1 (5-cyclopropyl-1-methyl-1 H-pyrazole-3- H), 0.87 - 1.06 (t, 2 H), 0.50 - 0.71 yl)-amide 5-(6,7-dihydro-5H-pyrrolo|3,4- (t, 2 H) a|Ipyrimidine-4- yloxy)-indole-1- I I carboxylic acid fe more) E ty 7x ВХ d (DMSO-dv) 6 parts/million 8.55 (5.1 H),

M. Zh M Mt 8.30 (a, 9U-8.84 Hz, 1 H), 8.17 (a,

Y shu uU-3.79 Hz, 1 H), 7.46 (a, 9-2.27 Hz, 1 z7-Ao M about H), 7.14 (ad, uU-9.09, 2.53 Hz, 1 MH), 444.0

H 7.07 (5.1 H), 6.75 (a, 9U-3.79 Hz, 1 (1-methyl-5-trifluoromethyl-1 H-pyrazole- | H), 4.03 - 4.16 (t, 4 H) 3.95 (5, C H).

3-yl)-amide of 5-(6,7-dihydro-5H-pyrrolo3,4-9|pyrimidin-4-yloxy)-indole-1-carboxylic acid

Example 58 58-А. 4-Nitrophenyl ether of 5-(6-benzyloxymethylpyrimidin-4-yloxy)-indole-1-carboxylic acid.

O, M and / (6) (6) o-

OK

X cho (6) more

Sodium hydride (102 mg, 4.27 mmol, 60 95 in mineral oil), the resulting mixture is stirred for 1 hour. Then this reaction mixture is added to a solution of p-nitrophenyl chlorochromate in THF at 0"C. The mixture is stirred at 0"C for 1 hour. Then the reaction is quenched with water, the product is extracted with EtOAc (2x). The combined organic phases are washed with water, brine, dried over sodium sulfate, filtered, and the solvent is removed. The residue is purified using KFC (0-60 950 EOAc/heptane) and obtain the desired compound. MS (IR) t/2 496.9 (M.n1). 58-8. (5-Trifluoromethyl-2H-pyrazol-3-yl)y-amide 5-(6b-benzyloxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid.

El chem

MN ss, (6) (6)

M th ef)

Yes, I am

Man (348 mg, 8.70 mmol, 60 95 in mineral The mixture is stirred at 0 "C for 1 hour. 5-(6β-Benzyloxymethylpyrimidin-4-yloxy)-indole-1-carboxylic acid 4-nitrophenyl ether (1440 mg, 2.90 mmol) in THF (10 mL) was then added. The resulting mixture is stirred overnight. Then the reaction is stopped with a saturated aqueous solution of ammonium chloride. The product is extracted with EtOAc (2x). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and the solvent was removed. The residue is purified by KFC (0-70 90 EOAc/heptane) and the desired compound is obtained. MS (IER) t/2 509.0(M-1). 58-06. (5-Trifluoromethyl-1H-pyrazol-3-yl)-amide of 5-(6-hydroxymethylpyrimidin-4-yloxy)-indole-1-carboxylic acid.

E E N

E M

M and (6) on

M th ef)

F o pc

A solution of 5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (5-trifluoromethyl-2H-pyrazol-3-yl)-amide (150 mg, 0.295 mmol) and TFC (1.5 ml ) are stirred at 110 "C for 1.5 hours.

After removing the excess TFC, the residue is neutralized with a saturated aqueous solution of sodium bicarbonate. Then the mixture is extracted with EtOAc (2x). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and the solvent was removed.

The residue is purified using KFC (0-100 96 EOAc/heptane) and the desired compound is obtained. MS (ER) t/2 418.9(M-1). 58-00. (5-Trifluoromethyl-2H-pyrazol-3-yl)y-amide of 5-(b-methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid. about CE

SS at 7

M. M. MN

(5-Trifluoromethyl-1H-pyrazol-3-yl)-amide 5-(b-hydroxymethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (50 mg, 0.120 mmol) is dissolved in THF (5 ml) and at 0 "С add TEA (0.033 ml, 0.239 mmol), then M5Cl (0.014 ml, 0.179 mmol). The mixture is stirred at 0 "C for 0.5 h. Then the mixture is diluted with EtOAc and washed with water, saline solution, dried over sodium sulfate, filtered and the solvent is removed. Then the residue without treatment is used in the next stage.

To a solution of methanesulfonic acid 6-11-(b-trifluoromethyl-1H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy|-pyrimidin-4-ylmethyl ether (50 mg, 0.101 mmol) in THF (5 ml ) add methylamine in Meon (0.5 mL, 2.0 M). The mixture is stirred at RT for 3 days and then the solvent is removed.

Next, the residue is purified using semi-preparative HPLC and the desired compound is obtained. MS (IER) t/ 431.9 (M--1); "H NMR (400 MHz, Meob) 5 ppm 8.65 (5, 1 H), 8.43 (a, U-9.09 Hz, 1 H), 7.89 (a, 9-3 .79 Hz, 1 N), 7.41 (a, 9-2.53 Hz, 1 N), 7.11 (aa, U-8.97, 2.40 Hz, 1 N), 7.00 ( 5, 1 H), 6.74 (a, 9-3.54

Hz, 1 H), 6.52 (5, 1 H), 3.82 (5, 2 H), 2.44 (5, C H).

The following compounds are obtained by a similar method. 58-E. 5-(6b-methylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (5-tert-butylisoxazol-3-yl)-amide. (in)

To, H

J

M. m her 9

M ra she h o nn

MS (IER) t/ 421.0 (M--1) H NMR (400 MHz, Meob) 5 ppm 8.65 (5.1 H), 8.37 (a, U-8.84 Hz , 1

H), 7.91 (a, 9U-3.54 Hz, 1 H), 7.41 (a, 9-2.27 Hu, 1 H), 7.12 (aa, U-8.84, 2 ,27 Hz, 1 N), 7.00 (5, 1 N), 6.74 (a, 9U-3.79 Hz, 1 N), 6.65 (5, 1 N), 3.79 (5 , 2 H), 2.41 (5, C H), 1.39 (5, 9 H). 58-B. 5-(6-Methylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (3-tert-butylisoxazol-5-yl)-amide. inv;

WITH

M X-m x (c); N

MS (ER) t/ 421.1 (M--1); "H NMR (400 MHz, Meob) 5 ppm 8.65 (5, 1 N), 8.42 (y, 2-91 Hz, 1 N), 7.93 (9, 9-3.8 Hu, 1 H), 7.36 (a, 9U-2.3 Hu, 1 H), 7.05 (aa, 2U-8.8, 2.3 Hu, 1 H), 6.94 (5, 1 H), 6.64 (a, 9-3.8 Hz, 1 H), 6.30 (5, 1 H), 3.94 (5, 2 H), 2.54 (5, C H) , 1.34 (5.9 H). 58-22. 4-Fluoro-(5-tert-butylisoxazol-3-yl)u-amide. 5-(b-methylaminomethyl-pyrimidin-4-yloxy)-indol- 1- carboxylic acid o m o M

M with 7 x x o M

IS

MS (IER) t/2 439.1 (M-e1); "H NMR (400 MHz, Meob) 5 parts/million 8.66 (y, 9U-1.01 Hz, 1 H), 8.19 (a, 9-3.79 Gu, 1 H), 8, 15 (a, 9-9.09 Hu, 1 H), 7.28 (5, 1 H), 7.22 (a, 9-1.01 Hu, 1 H), 6.67 (a, 9- 3.79 Hu, 1 H), 6.67 (5, 1 H), 3.79 (5, 2 H), 3.91 (5, Z H), 1.34 (5.9 H). 58 -H.(5-Tert-butyl-1H-pyrazol-3-yl)-amide 4-fluoro-5-(b-methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid

N

M m o M

M o 7

M M

X in (in) M

IS

MS (IER) t/2 439.1 (M-e1); "H NMR (400 MHz, Meob) b frequency/million 8.63 (y, 9U-1.01 Hz, 1 H), 8.13 (a, 9U-9.09 Gu, 1 H), 7, 90 (a, 9-3.79 Hz, 1 H), 7.17 (aa, 9-8.84, 7.58 Hz, 1 H), 7.13 (c, 1 H), 6.80 ( a, 9U-3.79 Hz, 1

Н), 6.38 (5, 1 Н), 3.83 (5, 2 Н), 2.43 (5, З Н), 1.396 (5, 9 Н).

Example 59 59-А. 5-(6-Benzyloxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (5-tert-butyl-1H-pyrazol-3-yl)-amide.

N

M what S

AND

(6) (6) ate

CO

F o pc

To a solution of 5-(6b-benzyloxymethylpyrimidin-4-yloxy)-indole-1-carboxylic acid 4-nitrophenyl ether, compound of example 58A (100 mg, 0.201 mmol) and 5-tert-butyl-1H-pyrazol-3-ylamine ( 56.1 mg, 0.403 mmol) in THF (5 mL) add diisopropylethylamine (0.11 mL, 0.604 mmol). The resulting mixture is stirred at 65 °C overnight. After cooling to room temperature, the reaction is quenched with water. The product is extracted with EtOAc (2x). The combined organic layers are washed with water, brine, dried over sodium sulfate, filtered and the solvent is removed. The residue is purified with the help of KFC (0-60 96 EOAc/heptane) and obtain the desired compound. MS (IR) t/2 497.0 (M--1) 59-8. yl)-amide of 5-(6-methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid. (c)

There is Z

MN

Mo 22 M sad en h o nn

Conversion of (5-tert-butyl-1H-pyrazol-3-yl-amide 5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid to (5-tert-butyl-2H-pyrazole-3 -yl)y-amide of 5-(b-methylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid is carried out similarly to that described above in example 580. MS

(IER) t/2 420.0 (M-1); "H NMR (400 MHz, MeOb) 5 ppm 8.65 (bBg. 5., 1 H), 8.35 (a, U-9.09 Hz, 1 H), 7.90 (a, 9-3.28 Hz, 1 H), 7.41 (Bg. 5., 1 H), 7.10 (a, 2U-8.84 Hz, 1 H), 6.99 (bBg. 5., 1 H), 6.72 (a, 9U-3.54 Hz, 1

H), 6.37 (bBg. 5., 1 H), 3.78 (Bi. 5., 2 H), 2.41 (rg. 5., Z H), 1.36 (ru. 5. , 9 H).

The following compounds are obtained by a similar method. 59-6. (5-Trifluoromethyl-1H-pyrazol-3-yl)-amide 4-fluoro-5-(6b-methylamino-methylpyrimidin-4-yloxy)-indole-1-carboxylic acid.

IS

And r;

Mao Zedong -

M. M. MN

M

! hmm x (in); N

MS (ER) t/2 450.0 (M--1); "H NMR (400 MHz, DMSO-dv) 6 ppm 8.73 (5.1 H), 8.32 (y, 9U-8.8 Hz, 1

H), 8.09 (a, 9-3.5 Hz, 1 H), 7.23 (5, 1 H), 7.20 (a, 2-83 Hz, 1 H), 6.77 (a , 9-3.5 Hz, 1 N), 6.54 (5.1 N), 4.02 - 4.14 (t, 1 N), 3.98 (5, 2 N), 2.45 ( c, Z H).

Example 60 6О-А. Tert-butyl-4-(1-(4-nitrophenoxy)carbonyl)-1H-indol-5-yloxy)-5,6-dihydropyridoy3,4- d9|Ipyrimidine-7(8H)-carboxylate. yes I) (c)

M (in)

To a solution of tert-butyl-4-(1H-indol-5-yloxy)-5,6-dihydropyrido|3,4-4|pyrimidine-7(8H)-carboxylate, compound of example 31-C (1 g, 2, 73 mmol) in 20 ml of THF at 0 "С add sodium hydride (0.164 g, 4.09 mmol, 60 95 in mineral oil). After 1.5 hours, add a solution of 4-nitrophenyl chloroformate (1.65 g, 8.19 mmol) in THF (10 mL). The mixtures were allowed to warm to RT and stirred overnight and then quenched with ice water and extracted with EOAc. The combined organic layers were washed with water and brine and then dried (Mg25O4) and concentrated. Next, the residue is purified using KFC (20-80 95 EIOAc/heptane) and the desired compound is obtained. "H NMR (400 MHz,

SOFI") b freq./million 8.54 (5, 1 N), 8.34 - 8.43 (t, 2 N), 7.79 (a, U-3.8 Hz, 1 N), 7 .49 - 7.57 (t, 2 N), 7.41 (y, 9-2.3 Hz, 1 N), 7.17 (yes, 9-9.0, 2.4 Hz, 1 N) , 6.75 (a, 9U-3.5 Hz, 1 N), 5.31 (5, 1 N), 4.65 (5.2 N), 3.80 (i, y-5.8 Gu , 2 N), 2.95 (I, 9-5.6 Hz, 2 N), 1.53 (5, 9 N). 60-B8. Tert-butyl-4-(1-(3-(tert-butyldimethylsilyloxy)methyl)-5-trifluoro-methyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyridoyi3,4-4|pyrimidine- 7(8H)-carboxylate.

IS

E E ge o xx ra 1 jui

M u o

M

M o nn ke

To a solution of 2,2,6,6-tetramethylpiperidine (0.067 mL, 0.391 mmol) in THF (1.5 mL) at -78 C, p-Vygi (0.13 mL, 0.331 MMoO) was added. In 15 minutes. add 3-(tert-butyldimethylsilanyloxymethyl)-5-trifluoromethylphenylamine. In another 15 minutes. at -78 "C, a solution of tert-butyl-4-(1-((4-nitrophenoxy)carbonyl)-1H-indol-5-yloxy)-5,6-dihydropyridoyi3,4-d9|pyrimidine-7( 8H)-carboxylate in THF (3 ml). After 1 h, the reaction mixture is diluted with

EtOAc, the reaction is quenched with ice water and extracted with EtOAc. The combined organic layers were washed with water, brine and dried (Mag25O4) and concentrated. The residue is purified using KFC (10-60 96 EOAc/heptane) and the desired compound is obtained. MS (ER) t/2 698.3 (M-H1).

60-60. (3-Hydroxymethyl-5-trifluoromethylphenyl)-amide 5-(5,6,7,8-tetrahydro-pyrido[3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

E.S

Ge) Z vav;

M. and on

M (in) N

N

Tert-butyl-4-(1-(3-(tert-butyldimethylsilyloxy)methyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-4| pyrimidine-7(8H)-carboxylate is treated with 96HFK in DCM for 1 hour. The solution is then concentrated and the residue is taken up in EtOAc, washed with saturated sodium bicarbonate solution and brine and then dried (Mg5Ox4) and concentrated. Next, the residue is purified using HPLC (C18; 12-42 965 ACN/H2O with the addition of 0.1 96 TFC) and the desired compound is obtained. MS (IER) t/2 484.1 (M-1); "H NMR (400 MHz, DMSO-av) b frequency/million 10.37 (5.1 N), 8.40 (5.1 N), 8.27 (9.9-9.0 Hz, 1 H), 8.13 (a, U-3.7 Hz, 1 H), 7.97 (a, U-10.9 Hz, 2

H), 7.38 - 7.49 (t, 2 H), 7.12 (da, 9U-9.0, 2.4 Hz, 1 H), 6.79 (a, 9-3.7 Gu , 1 N), 5.50 (i, 9U-5.7 Hz, 1 N), 462 (90, 9-5.7 Hz, 2 N), 3.82 (5, 2 N), 3.03 (Y, 9-5.7 Hz, 2 N), 2.72 (Y, 9-5.5 Hz, 2 N).

The following compounds are obtained by a similar method. 60-0. (3-Hydroxymethyl-5-trifluoromethylphenyl)-amide (g)-5-(b-methyl-5,6,7,8-tetrahydropyridoyl3,4-a|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

M.O ES vav;

M. Z her on

M (6) N

N

MS (IER) t/2 498.1 (M--HT1); "H NMR (400 MHz, DMSO-dv) 5 ppm 10.35 (5, 1 N), 8.40 (5, 1 N), 8.27 (a, 9-91 Hu, 1 N) , 8.13 (a, 9U-3.8 Gu, 1 N), 7.97 (a, 9-11.1 Hz, 2 N), 7.40 - 7.46 (t, 2 N), 7 ,11 (yes, U-9.0, 2.4

Hz, 1 H), 6.78 (y, 9-3.5 Hz, 1 H), 5.48 (Her, 9-5.7 Hz, 1 H), 4.62 (a, 9U-5, 6 Hz, 2 H), 3.79 - 3.96 (t, 2 H), 2.90 - 3.03 (t, 1 H), 2.85 (ai, 9-171, 3.4 Gu, 1 H), 2.29 - 2.38 (t, 1 H), 1.22 (a, 9-6.3 Hz, C H). 60-E. (5-Trifluoromethyl-1H-pyrazol-3-yl)-amide 4-fluoro-5-(5,6,7,8-tetrahydro-pyridoyl3,4-4|pyrimidin-4-yloxy)-indol-1- carboxylic acid.

And in vva;

J

M. mo 1 MN already M

M o nn

N

MS (IER) t/2 462.3 (M--1); "H NMR (400 MHz, Meob) b freq./million 8.38 (Bg. 5., 1 H), 8.13 - 8.24 (t, 1

H), 7.83 - 7.96 (t, 1 H), 7.12 - 7.24 (t, 1 H), 6.81 - 6.87 (t, 1 H), 6.54 (Bi 5., 1 N), 3.97 (5.2 N), 3.14 - 3.24 (t, 2 N), 2.92 (rg. 5., 2 N). 60-R. (5-Trifluoromethyl-1H-pyrazol-3-yl)-amide (g)-4-fluoro-5-(b-methyl-5,6,7,8-tetrahydropyridoyl3,4-a|pyrimidin-4-yloxy) -indole-1-carboxylic acid. Oh and wow

SSO and

M. My MN minds M

M o nn

N

MS (ER) t/2 476.1 (M--1); "H NMR (400 MHz, DMSO-dv) b parts/million 8.44 (5, 1 H), 8.24 (a, 9U-8.84 Gu, 1 H), 8.08 (a, 9U -3.79 Hz, 1 N), 7.22 (I, U-8.08 Hz, 1 N), 6.80 (a, U-4.04 Hz, 1 N), 6.57 (5, 1 N), 3.90-3.96 (t, 2 N), 3.07 (give, 9U-10.11, 6.06, 4.04 Hz, 1 N), 2.90, 2.94 (t, 1 H), 2.38-2.45 (t 1H), 1.24 (y, 2-4.04 Hz, ЗН).

Example 61 61-А. (5)-5-Methyl-tert-butyl ether of 4-oxo-3,4,5,7-tetrahydro-pyrrolo!3,4-d|pyrimidine-6b-carboxylic acid.

NM co

M o-4-

Ethoxycarbonylaminoacetic acid ethyl ether (38 g, 187 mmol) was added to a suspension of Mann (9.72 g, 243 mmol, 60 95 in mineral oil) in toluene (100 ml) at 0 C. The reaction mixture is stirred for 5 hours. at the same temperature. But-2-enoic acid ethyl ether (25.6 g, 224 mmol) was then added and the reaction mixture was allowed to warm to RT and stirred for another 2 h. Ethanol (30 ml) was added and then the reaction mixture was evaporated. Crude 1-tert-butyl-3-ethyl-2-methyl-4-oxopyrrolidine-1,3-dicarboxylate is dissolved in EN (1500 ml), then formamidine acetate (343 g, 1189 mmol) is added, then sodium ethoxide (47.2 g, 694 mmol). The reaction mixture is stirred at 90 "C for 8 h. Then the solvent is removed and a saturated solution of MNACI (200 ml), then DCM (1 L) is added to the crude substance. The aqueous layer is extracted twice with DCM. The organic substances are dried and evaporated. Crude the product is purified by FCX (from DCM/Meon 100:0 to 90:10) and the desired compound is obtained. MS (ER) t/2 252.2 (M-y1). 61-8. tert-butyl ether («( g)-4-(1H-indol-5-yloxy)-5-methyl-5, 7-dihydropyrroloY3,4-4|pyrimidine-6b-carboxylic acid. (6)

CO

M. 2 M

N

M

- about x

To a solution of 5-methyl-4-oxo-3,4,5,7-tetrahydropyrrolo|3,4-4|Ipyrimidine-6-carboxylic acid tert-butyl ether (1 g, 3.98 mmol) in acetonitrile (40 ml ) add RUVOR (2.69 g, 5.17 mmol), then

DBU (1.200 mL, 7.96 mmol). In 20 minutes. add 5-hydroxyindole (1.060 g, 7.96 mmol). The reaction mixture is stirred at RT overnight. Then the reaction mixture is evaporated, the crude product is introduced into a silica gel column and eluted with a mixture of heptane/ethyl acetate (from 100:0 to 60:40) and the desired compound is obtained. MS (ER) t/2 367.05 (M.n1). 61-S. (5)-5-Methyl tert-butyl ether 4-11-(3-trifluoromethylphenyl-carbamoyl)-1H-indol-5-yloxy|- 5,7-dihydropyrrolo|3,4-4|Ipyrimidine-6- carboxylic acid.

EC

Ge) av;

MO M

M otu )-o h

To a solution of 4-(1H-indol-5-yloxy)-o-methyl-5,7-dihydropyrrolo|3,4-4|pyrimidine-b-carboxylic acid tert-butyl ether (400 mg, 1.092 mmol) in THF ( 10 ml) at 0 "С add sodium hydride (74.2 mg, 1.856 mmol, 6095 in mineral oil). After 10 min. add 1-isocyanato-3-trifluoromethylbenzene (0.314 ml, 2.183 mmol) and allow the reaction mixture to warm to CT. After 2 h, a saturated solution of MNeCl in water (5 ml) is added. The organics are extracted with EtOAc (x3), dried and evaporated to give crude 4-(1-(3-trifluoromethylphenylcarbamoyl) 5-methyl-tert-butyl ether )-1H-indol-5-yloxy|-5, 7-dihydropyrrolo|Y3,4-4|pyrimidine-b-carboxylic acid MS (IER) t/2 554.9 (M-H1) 61-0. (3-Trifluoromethylphenyl)-amide (g)-5-(5-methyl-b,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

Che Ezb wav;

Mo M

M Hmm

N (6) N

To a solution of 4-(1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy|-5,7-dihydropyrrolo|3,4-4|Ipyrimidine-6-carboxylic acid 5-methyl-tert-butyl ether in DCM (20 ml), TFA (20 ml, 134 mmol) is added at 0 "C. After 30 min. the reaction mixture is heated to RT. Then the reaction mixture is evaporated and the crude product is dissolved in EIOAc. A few drops of MNAOH are added to the free base of the amine and then the mixture is evaporated. The crude product is introduced into a silica gel column and eluted with a mixture of DCM/Meon/lMnNaOHn (from 100:0:0 to 93:6:1) and racemic (3-trifluoromethylphenyl)-amide 5-(5-methyl) is obtained -b, 7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid. MS (IER) t/l 454.9 (M--1); "H NMR (400 MHz, Meorb) b frequency/million 8.50 (5.1 N), 8.33 (5.1 N), 8.06 (5.1 N), 7.94 (Bbg. 5. , 2 H) 7.57 (5, 1 H), 7.42 (Bg. 5., 2 H) 7.12 (a, 9-9.09 Hz, 1 H), 6.75 (a, 3 -3.03 Hz, 1 H), 4.70 (Bg. 5., 1 H), 4.10-4.22 (t, 2 H), 1.60 (y, 9U-6.57 Hz, From H.) The racemate is then separated using a chiral BE RH (column IA; 40 95 heptane, 60 95 ethanol) and obtain the corresponding enantiomers 0-1 and 0-2. 61-0-1. (4)-(3-Trifluoromethylphenyl)-amide 5-(5-methyl-b,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

Vi-6.09 min.; MS (IER) t/2 454.9 (M--1); "H NMR (400 MHz, Meob) 5 parts per million 8.48 (5.1 N), 8.30 (a, 3-9.09 Hz, 1 N), 8.03 (5.1 N) , 7.687 (y, 9-3.54 Hz, 2 H), 7.52 (I, 9U-8.08 Hz, 1 H), 7.38 (y, 9-2.27 Hz, 2 H), 7.07 (yes, U-8.84, 2.27 Hz, 1 H), 6.67 (a, 9-3.79 Hz, 1 H), 4.66 (4, 9U-6.57 Hz , 1 H), 4.12-4.22 (t, 2 H), 1.56 (a, 9U-6.57 Hz, C H). 61-0-2. (-)-(3-Trifluoromethylphenyl )-amide of 5-(5-methyl-b,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

Ве7.71 min.; MS (ER) t/2 454.9 (M--1); "H NMR (400 MHz, meOob) b frequency/million 8.47 (a, 9-1.77 Hz, 1

H), 8.28 (ad, 9U-9.09, 1.77 Hz, 1 H), 8.02 (5, 1 H), 7.85 (ai, U-3.66, 2.40 Hz , 2 H), 7.49 (I, 9-7.83 Hz, 1 H), 7.36 (y, 9-2.02 Gu, 1 H), 7.38 (a, 9U-8.59 Hz, 1 H), 7.06 (yes, 9U-8.84, 2.27 Hz, 1 H), 6.65 (a, 9U-2.53 Hz, 1 H), 4.63 (a, 9-6.06 Hz, 1 N), 4.15 - 4.23 (t, 1 N), 4.05 -4.12 (t, 1 N), 1.55 (y, 9-6.57 Gu, Z N).

The following compounds are obtained by a similar method. 61-E. (2-Fluoro-5-trifluoromethylphenyl)-amide /(h5)-5-methyl-6b,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid

Che Ezb wav;

M. M

M Hmm

N o n E

MS (ER) t/2 472.9 (M--1); "H NMR (400 MHz, Meor) b frequency/million 8.49 (5.1 H), 8.29 (a, 9U-8.84 Gu, 1

H), 8.17 (a, 9U-6.82 Hu, 1 H), 7.89 (a, 9U-3.79 Hu, 1 H), 7.57 (aa, U-8.72, 1 ,39 Hz, 1 N), 7.29 - 7.45 (t,2 N), 7.10 (da, U-8.84, 2.02 Hz, 1 N), 6.73 (a, 9 -3.79 Hu, 1 H), 4.68 (a, U-6.48 Hu, 1 H), 4.20 (a, 9-1.77 Hz, 1 H), 4.06 - 4, 15 (t, 1 N), 1.58 (a, U-6.82 Hz, C H).

Example 62 6b2-A. (5-Tert-butyl-2H-pyrazol-3-yl)y-amide (g)-5-methyl-b,7-dihydro-5H-pyrroloi|3,4-4|pyrimidin-4-yloxy)-indole -1-carboxylic acid. there is also; ! their

M H-m N

N IF) N

To a solution of tert-butyl-4-(1H-indol-5-yloxy)-5-methyl-5H-pyrrolo|3,4-4|Ipyrimidine-6(7H)-carboxylate (150 mg, 0.409 mmol) in DMF ( 4 ml) at RT add di(1H-imidazol-1-yl)methanone (86 mg, 0.532 mmol), then TEA (0.34 ml, 2.46 mmol). After three hours 5-tert-butyl-1H-pyrazol-3-amine (342 mg, 2.46 mmol) was added at room temperature and the reaction mixture was stirred at RT for 48 h. Then add 1 n. a solution of HCI in water (2 ml) and EUAs (5 ml). The layers are separated and the aqueous layer is extracted 3 times with EtOAc. Organic substances are dried and evaporated. At 0" C, DCM (4 mL) and TFA (10 mL, 130 mmol) are added and the reaction mixture is allowed to warm to RT over 1 h. At this point the reaction is complete. The TFA/DCH is evaporated and the product is then transferred to EtOAc (100 mL) .

Add MNAOH (20 mL) followed by water. The organic substances are separated and the aqueous layer is extracted with EtOAc (2 times). Organic substances are dried and evaporated. The crude product is introduced into a column with silica gel (IZCO) and eluted with a mixture of DCM/Meon/lmnaon (from 100:0:0 to 93:6:1) and isolated (5-tert-butyl-2H-pyrazol-3-yl)- amide of 5-methyl-6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid. MS (IER) t/2 432.0 (M--1); "H NMR (400 MHz, Meob) 5 parts/million 8.50 (5.1

H), 8.33 (a, 9U-9.09 Hz, 1 H), 7.89 (y, 9-3.54 Hz, 1 H), 7.41 (a, 9-2.27 Hz, 1 H), 7.10 (aa, 9U-8.97, 2.40 Hz, 1

NO, 6.71 (y, 9-3.54 Hz, 1 H), 6.37 (5, 1 H), 4.71 (а, 9-6.57 Hz, 1 H), 4.10- 4.22 (t, 2 H), 1.60 (a, 9U-6.82 Hz, Z

N) 1.37 (5.9 N).

The following compounds are obtained by a similar method. 6b2-8. (5-Trifluoromethyl-2H-pyrazol-3-yl)-amide (5)-5-methyl-6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indol-1- carboxylic acid

E Y E wav; their

M H-m N

N IF) N

MS (ER) t/2 444.9 (M--1); "H NMR (400 MHz, Meor) b frequency/million 8.50 (5.1 H), 8.41 (a, 9-9.09 Hz, 1

H), 7.88 (9, 9U-3.79 Hz, 1 H), 7.43 (y, 9-2.27 Gu, 1 H), 7.14 (ad, 9U-8.97, 2 ,40 Hz, 1 N), 6.77 (a, 9-3.79 Hz, 2

NO, 4.71 (a, 9U-6.32 Hz, 1 H), 4.22 (a, 9-1.77 Hz, 1 H), 4.16 (a, 9U-1.26 Hz, 1 H), 1.60 (a, 9U-6.82 Hz, Z H).

Example 63 63-А. (3-Trifluoromethylphenyl)-amide 5-(b-methyl-6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid. still ES vav;

M. 2 M

M Hmm

M o nn 5-(6,7-Dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-M-(3-trifluoromethyl)-phenyl)-1H-indole-1-carboxamide (140 mg, 0.320 mmol) was suspended in 1,2-dichloroethane (5 mL) and formaldehyde (50 μL, 0.672 mmol) and acetic acid (36 μL, 0.629 mmol) and sodium triacetoxyborohydride (139 mg, 0.656 mmol) were added and the mixture heated at 60 "C overnight. The reaction mixture is cooled to RT, diluted with water, saline solution, and DCM. The organic phase is separated, dried and concentrated, and an oil is obtained, which is purified with the help of KFC (0-10 95 MHz/Meon:dxMm) and (3-trifluoromethylphenyl)-amide 5-(6b-methyl-6,7-dihydro-5H) is obtained -pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid. MS (ER) t/ 454.95 (M--1); "H NMR (400 MHz, DMSO-av) b frequency/million 10.38 (5.1 N), 8.56 (5.1 N), 8.27 (a, 9-9.09 Hz, 1 H), 8.09 -8.13 (t, 2 H), 7.96 (5, 1 H), 7.65 (I, U-8.08 Hz, 1 H), 7.48 - 7, 51 (t, 2 H), 7.15 (da, U-8.97, 2.40 Gu, 1 H), 6.80 (a, 9U-3.79 Hz, 1 H), 3.91 ( 5, 4 H), 2.52 (5, C H).

The following compounds are obtained by a similar method.

MS (ER)

Structure/chemical name IH NMR (400 MHz) t/2

MAN

Me oh gas

TY If; (DMSO-av) 6 ppm 10.38 (5.1 N), 8.56

M. 2 M (5, 1 H), 8.27 (a, 9U-9.09 Hz, 1 H), 8.09 - r 8.13 (t, 2 H), 7.96 (in, 1 H), 7.65 (5.1 H), 63-V M o nn 7.48 - 7.52 (t, 2 H), 7.15 (da, U-8.84, 2.27 468.9 y ; Gu, 1 H), 6.80 (a, 9U-3.79 Hz, 1 H), 3.92 - " 3.96 (t, 4 H) 2.75 (da, U-7.33 Hz . 3,4-9-Ipyrimidin-4-yloxy)-indole-1-carboxylic acid

Che gas vav;

M. Zh M (DMSO-dv) 6 ppm 10.38 (5.1 N), 8.56

M (5, 1 N), 8.27 (a, 9U-9.09 Hz, 1 N), 8.09 -

M M 8.13 (t, 2 H), 7.96 - 7.99 (t, 1 H), 7.62 - 63-С /- On 7.67 (t, 1 H), 7.48 - 7.52 (t, 2 H), 7.15 483.0 (ad, 9U-8.84, 2.53 Hz, 1 H), 6.680 (a, 9-3.79 (3-trifluoromethylphenyl)-amide 5-(6- Hu, 1 H), 3.98 (a, 9U-13.14 Hz, 4 H), 2.83 (c, isopropyl-6,7-dihydro-5H-pyrrolo|3,4- | 1 M)» 1.07 - 1.14 (4.9U-6.32 Hz, 6 H). 9|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid

IS

E E g more X E (DMSO-dv) 6 ppm 8.56 (5.1 N), 8.27

M ru M (a, 9U-9.09 Hz, 1 H), 8.09 (a, U-3.79 Hz, 1 H), 7.91 (5, 1H) 7.55-7.55 ( t, 1 H), 7.40 - 7.55 63-0 M rya (t, 2 H), 7.14 (yes, U-8.97,2.40 HZ, 1 H), 472.0 x o nn 6.79 (a, 9-3.79 Hz, 1 H), 3.90 (5, 4 H), 2.52 (2-fluoro-3-trifluoromethyl-phenyl)-(5, 3 H) . 5-(6-methyl-b,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid amide

M (c); and se IF; i (DMSO-dv) 6 ppm 11.28 (5.1 N), 8.56

M. Z. M |8; (5, 1 N), 8.30 (5, 1 N), 8.17 (a, 9-3.79 Hz, 1 r M NO, 7.47 (0, 9-2.27 Hz, 1 N ), 7.15 (aa, 63-E M o i y-8.97, 2.40 Hz, 1 H), 6.76 (a, 9-3.79 Hz,1 | 433.1 i: H) , 6.68 (5, 1 H), 3.90 (a, 9-1.52 Hz, 4 H), (b-tert-butylisoxazol-Z-yl)-amide 5- With H), 1.34 (5, 9 H). x (DMSO-dv) 6 ppm 11.28 (bBg. 5., 1 N),

СХ M y o 8.56 (5, 1 H), 8.29 (a, 9U-9.09 Hz, 1 H), 8.17 (a, 9U-3.54 Hz, 1 H), 7, 47 (a, 9-2.27 Hz, 1 N),

M r 7.15 (yes, U-8.97, 2.40 Hz, 1 H), 6.77 (y, 63-E o n 9U-3.79 Hz, 1 H), 6.68 (5 . , 9U-11.31, 1.89 Hz, 2 H), 2.71 (5.1 " I I H), 1.85 (9, 9-1.26 Hz, 2 H), 1.48 ( a, 9U-4.04 (5-tert-butylisoxazol-3-yl)-amide 5-Hz, 2 H), 1.34 (5, 9 H).

Ib-"tetrahydropyran-4-yl)-6,7-dihydro-

BN-pyrrolo!|3,4-4|pyrimidin-4-yloxy|- indole-1-carboxylic acid

E ge g y; E (DMSO-dv) 6 ppm 8.52 (5, 1 N), 8.31 (a, 9U-8.84 Hz, 1 N), 8.01 (t, 1 N), 7, 93 (y, in M 9U-3.79 Hz, 1 N), 7.57 (5, 1 N), 7.34 - 7.50

M cancer (t, 2 H), 7.13 (da, U-8.97,2.40 Hz, 1 H), 63-a o nn 6.76 (a, 9U-3.79 Hz, 1 H ), 4.02 (a, 9-17 43 558.0 ro Hz, 4 H), 3.84 - 3.96 (t, 1 H), 3.71 - 3.81 (t, C H), 3.64 - 3.71 (t, 2 H), 3.53 - 3.64 97 (t, 2 H), 3.33 - 3.53 (t, 1 H). (2-fluoro-3-trifluoromethyl-phenyl)-amide 5-(6-1,4-dioxynan-2-ylmethyl-

6,7-dihydro-5H-pyrrolo|3,44|pyrimidin-4-yloxy)-indole-1-carboxylic acid

M y; (DMSO-dv) 6 ppm 12.13 (5, 1 N), i a 10.57 (5, 1 N), 8.56 (5, 1 N), 8.30 (a, 9U- 8.84

M. M MN hc n),8.17 (Bk. 5., 1 NU, 7.44 (a, 952.53 rak M Gu, 1 H), 7.11 (aa, U-8,84,2 .27 Hz, 1 H), 63-H M o nn 6.71 (a, 9-3.79 Hz, 1 H), 6.29 (bBg. 5., 1 H), 4441 u; 3.92 (a, 9-1.52 Hz, 4 N), 2.75 (ad, U-7.07 Hz, 2 N), 1.41 (5.3 N), 1.11 4, 9-7.20 Hz, Z H), (5-(1-methylcyclopropyl)-1H-pyrazole-| 0.86 - 1.03 (t, 2 H), 0.78 (t, 2 H)

5-(6-ethyl-6,7-dihydro-5H pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid 3-yl|-amide

M y; (DMSO-dv) 6 parts per million 12.13 (bBg. 5., 1 N), i B 10.57 (5, 1 N), 8.55 (5, 1 N), 8.30 (a , 9U-8.84

M. M MN Hz nu, 8.17 (9, 923.28 Hz, 1 N), 7.44 (a, rya M 9-2.27 Hz, 1 N), 7.11 (da, U-8 .84, 2.53 Hz, 1 63rd M o nn NI, 6.71 (a, 9-3.79 Hz, 1 N), 6.29 (5.1 N), 458.1 /- 3 .83 - 4.08 (t, 4 H), 2.68 - 2.93 (t, 1 H), 1.41 (5, Z H), 1.12 (a, U-6.32 Hz, 6 H), 0.88 (5-(1-methylcyclopropyl)-1H-pyrazole-|-- 0.97 (t, 2 H), 0.63 - 0.80 (t, 2 H)

Z-yl|-amide 5-(6-isopropyl-b, 7-dihydro-

BN-pyrrolo!|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid more)

TY - x (DMSO-dv) 6 parts per million 12.13 (bBg. 5., 1 N),

M. i M 7SMno 110.57 (Bk. 8., 1 H), 8.56 (5, 1 H), 8.30 (t, 1 zhd H), 8.16 (t, 1 H), 7 .44 (t, 1 H), 7.12 (t, 1 63-U M Hm H), 6.70 (t, 1 H), 6.29 (5, 1 H), 3.90 (in, 4 430.1 h o n H), 2.55 (5, Z H), 1.40 (5.3 H), 0.92 (t, 2

I5-(1-methylcyclopropyl)-1H-pyrazole-H), 0.78 (t, 2 H)

5-(6-methyl-b,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid 3-yl|-amide

Example 64 6b4-A.. (3-Trifluoromethylphenyl)-amide 5-I(6-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy|-indole -1-carboxylic acid.

Che gas vva;

M.O 22 U y (c) H on 5-(6,7-Dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-M-(3-(trifluoromethyl)-phenyl)-1 N-indole-1-carboxamide (125.9 mg, 0.287 mmol) was dissolved in DMF (5 mL) and TEA (80 μL, 0.577 mmol) was added, followed by 2-bromoethanol (80 μL, 1.133 mmol). The solution is stirred at RT overnight. Then the reaction mixture is concentrated and absorbed on silica gel and purified with the help of KFC (0-10 9, 96 MNa. in Meon:DHM) to obtain 5-(6-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo! 3,4-4|pyrimidin-4-yloxy)-M-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide. MS (IER) t/2 484.0 (Ma1); "H NMR (400

MHz, DMSO-av) 6 parts/million 10.38 (5, 1 N), 8.56 (5, 1 N), 8.27 (a, 9-9.09 Hz, 1 N), 8, 09 - 8.14 (t, 2 N), 7.97 (a, 9-7.58 Hz, 1 N), 7.65 (I, 9-8.08 Hz, 1 N), 7.48 - 7.52 (t, 2 H), 7.15 (ad, 9-8.84, 2.53 Hz, 1 H), 6.80 (y, 9-3.54 Hz, 1 H), 4, 57 (I, 9-5.56 Hz, 1 H), 3.98 - 4.03 (t, 4 H) 3.58 (ad, U-6.06 Hz, 2 H), 2.82 (i , 9-6.06 Hz, 2

N).

The following compounds are obtained by a similar method.

MS (ER)

Structure/chemical name IN NMR (400 MHz) t/2

MAN sr wk M in (meob) 5 parts/million 10.27 (5.1 N), 8.56

CEa (5, 1 H), 8.24 (y, 9U-8.84 Hz, 1 H), 8.09 (a,

M Hm 9-3.79 Hz, 1 H), 7.94 (5, 1 H), 7.70 (5, 1 o n E H), 7.49 (a, 9-2.02 Hz, 2 H), 7.15 (aa, 64-V / 9-9.09, 2.27 Hz, 1 H), 6.81 (а, 9-3.79 Hz, 502.0

OH 1 H), 4.56 (Her, U-5.43 Hz, 1 H), 3.90 - 4.08

I I (t, 4 H), 3.58 (4, Y-5.89 Hz, 2 H), 2.82 (y, (2-fluoro-3-trifluoromethylphenyl)-amide 5-uCh-6.06 Hz, 2 N)

1b-(2-hydroxyethyl)-6, 7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy|-indole-1-carboxylic acid

М. 8.84 Hz, 1 H), 8.03 (a, 9-3.79 Hz, 1 H), 7.36 (j, 9-2.53

M rda Hz, 1 N), 7.07 (aa, U-8.97, 2.40 Hz, 1 N), ba-s / o nn 6.66 (a, U-3.79 Hz, 1 N ), 6.61 (5.1 N), 463 4 3.95 - 3.98 (t, 2 N), 3.90 (I, 9-2.27 Hz, 2 "

H), 3.60 (ad, 9-5.56 Hz, 2 H), 3.42 - 3.46 on (t, 1 H), 2.82 (Y, 9U-5.81 Hz, 2 H ), 1,21 - (o-tert-butylisoxazol-3-yl)-amide 5-I6-11,27 (t, 9 H) (2-hydroxyethyl)-6, 7-dihydro-5IN-pyrrolo|3, 4-4|pyrimidin-4-yloxy|-indole-1-carboxylic acid

There are also;

MiO 2 M t o (DMSO-av) 6 parts/million 8.55 (5.1 N),

X- M 8.46 (a, U-8.59 Hz, 1 N), 8.11 (a, 9U-3.54

Oh! their Gu, 1 H), 7.38 (a, 9-2.27 Hz, 1 H), 7.04 64-o / (da, 9-9.09, 2.53 Hz, 1 H), 6 .63 (5.1 N), 477 6.59 (Bu. 5., 1 N), 3.96 (5.4 N), 3.50 (i, ' (o) 9-5.81 Hz, 2 H), 3.26 (5, C H), 2.89 (i, / 3-5.68 Hz, 2 H), 1.31 - 1.36 (t, 9 H) (b-tert- butylisoxazol-3-yl)-amide 5-I(6-(2-methoxyethyl)-6, 7-dihydro-5H- pyrrolo|C 44|pyrimidin-4-yloxy|-indole-1- carboxylic acid

M. o is If; A (DMSO-ov) b frequency/million 10.57 (bg. 5., 1

M. z M MN H), 8.56 (5, 1 H), 8.28 (y, 9U-8.59 Hz, 1 r sh- H), 8.15 (5, 1 H), 7, 44 (a, 9-2.27 Hz, 1

M o her NU, 7.11 (yes, 9U-9.09, 2.53 Hz, 1 H), 6.68 6b4-E (5, 1 H), 6.29 (ri. 5.,1 H ), 4.00 (5.4 N), 460.1 / 3.58 (4, U9-5.56 Hz, 2 N), 2.78-2.80 (t, 2

OH H), 1.41 (5, C H), 0.93 (t, 2 H), 0.78 (t,

I5-(1-methylcyclopropyl)-1H-pyrazol-3-2B)yl|-amide 5-(6-(2-hydroxyethyl)-b, 7-dihydro-5H-pyrroloi|3,4-4|pyrimidine -4-yloxy|-indole-1-carboxylic acid

Example 65 65-A.. 14-1-(3-Trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-5,7-dihydropyrrolo|3,4-4|pyrimidin-b-yl)y-acetic acid. what else; wav

Can

5-(6,7-Dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-M-(3-trifluoromethyl)-phenyl)-1H-indole-1 - carboxamide (121.9 mg, 0.277 mmol) was dissolved in DMF (5 mL) and TEA (200 μL, 1.435 mmol) was added followed by tert-butylbromoacetate (101 μL, 0.693 mmol).The solution was stirred at RT overnight.

The reaction mixture is concentrated and then diluted with DCM (10 mL) and cooled to 0 °C. TFA (5 mL) is then added and the ice bath is removed and the reaction mixture is stirred at room temperature. The reaction mixture is concentrated, basified with ammonium hydroxide and diluted with ethyl acetate. . The solution is then treated with 1 N HCl. The ethyl acetate is removed, dried and concentrated to give a residue. The residue is dissolved in DMSO and purified by HPLC (C18; 200-100 95 ACN/H:O with the addition of 0.1 95 tFCq and 14-(1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-5, 7-dihydropyrroloi|3,4-d|pyrimidin-b-yl-acetic acid is obtained. MS (IER) t/2 498.9 (M--1); "H NMR (400 MHz, meob) b freq./million 8.50 (5.1 H), 8.32 (a, 9-8.84

Hu, 1 H), 8.06 (5, 1 H), 7.88 - 7.95 (t, 2 H), 7.57 (1, 97.96 Hu, 1 H), 7.40 - 7 .45 (t, 2 H), 7.12 (aa, 2-9.09, 2.02 Hz, 1 H), 6.74 (a, 9-3.79 Hz, 1 H), 4.19 (a, 9U-9.35 Hz, 4 H), 3.43 (5, 2H).

Example 66 66-А. (3-Trifluoromethylphenyl)-amide 5-(6-carbamoylmethyl-6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

Che ES vav;

Mi 22 u u o H 9) MH, 5-(6,7-Dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-M-(3-«"trifluoromethyl)-phenyl)-1 N-Indole-1-carboxamide (217 mg, 0.494 mmol) was dissolved in DMF (5 mL) and TEA (160 μL, 1.15 mmol) was added, followed by 2-bromoacetamide (250 mg, 1.81 mmol). at CT for 1 h. The reaction mixture is concentrated and the residue is absorbed on silica gel and purified with the help of KFC (0-10 95.95 MNa in MeonH:DXM) to obtain (3-trifluoromethylphenyl)-amide 5-(b-carbamoylmethyl-b, 7-dihydro-

BN-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid. MS (IER) t/» 497.9 (M--1); "H NMR (400

MGu, Meob) 5 parts/million 10.38 (bg. 5., 1 H), 8.58 (5, 1 H), 8.27 (a, 9-8.84 Hz, 1 H), 8 ,09 -8.13 (t, 2 H), 7.96 (v, 1 H), 7.65 (I, U-8.08 Gu, 1 H), 7.48 - 7.51 (t, 2 H), 7.38 (Bug. 5., 1 H), 7.09 - 7.17 (t, 2 H), 6.80 (a, 9-3.03 Gu, 1 H), 4, 12 (aa, 9-10.61, 2.02 Gu, 4 N), 3.38 (5.2 N).

The following compounds are obtained by a similar method.

MORE and MS (ER)

ST Styuaeniniany | I don't know 1

Eh

Gee)

Tj t If; and (DMSO-av) b parts/million 10.27 (5.1 N),

M. M 8.58 (5.1 N), 8.27 (5.1 N), 8.09 (a,

KhM 93.79 Gu, 1 H), 7.96 (5, 1 H), 7.66 (Bg. 66-V M about her 5.1 H), 7.44 - 7.52 (t, 1 Н), 7.14 (da, 515.1 3-8.84, 2.53 Hz, З Н), 6.79 (а, 9У-3.28 о-и Hz, 1 Н), 4.11 (aa, 9U-8.34, 2.02 Hz, 4

MH, H), 3.34 - 3.43 (t, 2 H) (2-fluoro-3-trifluoromethyl-phenyl)-amide 5-(6-carbamoyl-methyl-6b,7-dihydro-5H-

ore og of 1-carboxylic acid (c) Y i

SSO

! (DMSO-dv) 6 ppm 10.27 (5.1 N),

M M 8.58 (5, 1 H), 8.26 (5, 1 H), 8.09 (a,

Measure U-3.79 Hz, 1 N), 7.95 (5, 1 N), 7.67 (bBg. o nn 5., 1 N), 7.48 (overlap, n, 2 N) 66 -C B; 7.13 (aa, 9-9.09, 2.53 Hz, 1 H), 6.80 (а, 529.0 9) 3-3.79 Hz, 1 H), 4.09 (aa, 9U -7.45, 1.89

IN HC, 4 H), 3.40 (5, 2 H), 2.63 (a, 9-4.55

Hz, Z H) (2-fluoro-3-trifluoromethyl-phenyl)-amide 5-(b-methyl-carbamoylmethyl-b, 7-dihydro-5H-pyrroloi|3,4-4|pyrimidin-4-yloxy)- indole-1-carboxylic acid (c)

There is U va IF; (DMSO-dv) 6 ppm 11.28 (5.1 N),

M I 8.57 (5, 1 H), 8.30 (5, 1 H), 8.17 (y,

M M uU-3.79 Hz, 1 H), 7.47 (a, 9-2.53 Hz, 1 -/ On NU, 7.15 (ad, U-8.97, 2.40 Hz, 1 H), 6.77 4761 o (a, 9U-3.79 Gu, 1 H), 6.68 (5, 1 H), 4.09 - "

MH 4.15 (t, 4 H), 3.38 (5.2 H), 1.34 (5.9 2 H (b-tert-butylisoxazol-3-yl)-amide 5-(6-carbamoylmethyl- b, 7-dihydro-5iHn-pyrrolo|C 44|pyrimidin-4-yloxy)-indole-1-carboxylic acid fi cy ro M 7 o (DMSO-dv) 6 parts/million 10.11 (5.1 N ), s 8.54 (5, 1 N), 8.43 (a, 9U-9.09 Hz, 1 N),

Measured 8.19 (a, 9U-3.79 Hz, 1 H), 7.44 - 7.51 o nH (t, 1 H), 7.22 (da, 9-8.97, 2.40 Hz, 1 66-E -/ H), 6.81 (a, 9U-3.79 Hz, 1 H), 6.76 (5, 1 490.4 o H), 4.21 (1, 9- 2.15 Hz, 2 N), 4.14 (i,

Y 22.27 HC, 2 H), 3.48 (5.2 H), 2.77 - 2.81 (t, C H), 1.42 (5.9 H) (b-tert-butylisoxazole- 3-yl)-amide 5-(6- methylcarbamoyl-methyl-b, 7-dihydro-

BN-pyrrolo!|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid

Example 67 67-А. 4-(4-fluoro-1-(4-fluoro-3-trifluoromethylphenyl-carbamoyl)-2-methyl-1H-indol-5-yloxy|-pyridine-2-carboxylic acid methyl ester.

IS

! In Z

A 1 M solution of HINMOZ5 in THF (4.33 ml, 4.33 mmol) at -78 "С is added to the solution of methyl-4-(4-fluoro-2-methyl-1H-indole-5 -yloxy)picolinate (1 g, 3.33 mmol) in THF (50 mL). After 10 min, 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene (0.569 mL, 4.00 mmol) was added. After 40 min, a saturated aqueous solution of MNACI and EIOAc was added, and the aqueous layer was further extracted with EAc (200 mL).

The combined organic phases were washed with brine (40 ml), dried over Ma»bO4 and concentrated in vacuo. The residue is purified by HPLC (3595-9090 EtOAc/heptane) and the desired compound is obtained. MS (IER) t/2 505.1 (M--1); "H NMR (400 MHz, DMSO-av) 6 ppm 11.02 (5, 1 H), 8.61 (y, 9-5.56 Hu, 1 H), 8.13 (aa, U -6.32, 2.53 Hz, 1 H), 7.96 (bBg. 5., 1 H), 7.60 (a, U-8.84 Hz, 1 H), 7.60 (I, U-9.73 Gu, 1 H), 7.43 (a, 9-2.53 Hz, 1 H), 7.20 - 7.26 (t, 2H), 6.67 (5, 1 H) , 3.84 (5, Z H), 2.59 (5, Z

N). 67-V. (4-Fluoro-3-trifluoromethylphenyl)-amide of 4-fluoro-5-(2-hydroxymethyl-pyridin-4-yloxy)-2-methylindole-1-carboxylic acid.

E t Z

M on o n

4-(4-Fluoro-1-(4-fluoro-3-trifluoromethylphenylcarbamoyl)-2-methyl-1H-indol-5-yloxy|pyridine-2-carboxylic acid methyl ester (450 mg, 0.890 mmol) was placed in THF (10 ml) and cooled to 0 °C.

Add a 1 M solution of OIVAG-H (diisobutylaluminium hydride) in hexanes (2.67 ml, 2.67 mmol). The reaction mixture is stirred at 0 "C for 40 minutes. Then the reaction mixture is allowed to warm to room temperature. After another 45 minutes, the LC still detects the intermediate aldehyde, so another 1 ml of 1 M OIVAG-N in hexanes is added.

After 1 hour to end the reaction, add another 3 ml of MeonH and MavBna (0.14 g, 3.70 mmol). The reaction mixture is stirred for 10 minutes. and then diluted with EOAc and HO and mixed with 10 g of sodium-potassium tartrate for 1 hour. The organic layer was washed with saline, dried over Ma»25O4 and concentrated in vacuo. The residue is purified using KFC (50 965-100 95 EIOAc/heptane) and the desired compound is obtained. MS (IER) t/2 477.9 (M-e1); "H NMR (400 MHz,

DMSO-dv) b freq./million 11.01 (5, 1 N), 8.36 (y, U-5.56 Hz, 1 N), 8.13 (aa, 9U-6.57, 2, 53 Gu, 1 H), 7.94 - 7.98 (t, 1 H), 7.56 - 7.62 (t, 2 H), 7.14 - 7.19 (t, 1 H), 6 .89 (a, 9U-2.53 Hz, 1 H), 6.85 (da, 9U-5.56, 2.53 Hz, 1 H), 6.65 (5, 1 H), 5.37 (I, Y-5.68 Hz, 1 H), 4.49 (a, 9-5.81 Hz, 2 H), 2.59 (5, C H). 67-60. 4-(4-Fluoro-1-(4-fluoro-3-trifluoromethylphenylcarbamoyl)-2-methyl-1H-indol-5-yloxy|-pyridin-2-ylmethyl ether of methanesulfonic acid.

IS

In Z

M

(4-Fluoro-3-trifluoromethylphenyl)-amide (4-fluoro-5-(2-hydroxymethylpyridin-4-yloxy)-2-methylindole-1-carboxylic acid) (370 mg, 0.775 mmol) was placed in dichloromethane ( 10 mL) and added methanesulfonyl chloride (0.15 mL, 1.92 mmol) and TEA (0.4 mL, 2.87 mmol). The reaction mixture is stirred at RT for 20 minutes. and then diluted with dichloromethane and a saturated aqueous solution of MNACI. The aqueous layer is additionally extracted with dichloromethane. The combined organic layers were washed with brine and dried over Mag5O4, filtered and concentrated to give the desired compound. MS (IER) t/2 555.8 (M--1) 67-00. (4-Fluoro-3-trifluoromethylphenyl)-amide 5-(2-cyclopropylaminomethyl-pyridin-4-yloxy)-4-fluoro-2-methylindole-1-carboxylic acid.

IS

! In Z

M

Methanesulfonic acid 4-(4-Fluoro-1-(4-fluoro-3-trifluoromethylphenylcarbamoyl)-2-methyl-1H-indol-5-yloxy|-pyridin-2-ylmethyl ether (80 mg, 0.144 mmol ) is placed in THF (2 ml) and cyclopropylamine (0.030 ml, 0.432 mmol) is added and the reaction mixture is stirred at 40 "C for 18 h.

Then DMF (0.2 ml) is added and the temperature of the reaction mixture is increased to 50 "C. After another 4 hours, according to LCMS analysis, the reaction ends. The reaction mixture is diluted with EtOAc and H2O. The aqueous layer is washed with EOAc (3x50 The organic layers are then washed with brine and dried over Mag505, filtered and concentrated in vacuo.

The residue is purified by KFC (0-7 96 MeonN with the addition of 595 MNz in DCM) and the desired compound is obtained. MS (ER) t/2 516.9 (M--1); "H NMR (400 MHz, DMSO-dv) 6 ppm 8.34 (y, 9-5.81 Hz, 1 H), 8.06 (ad, U-6.06, 2.53 Hz, 1 H), 7.85 - 7.98 (t, 1 H), 7.53 (a, 9U-8.84 Hz, 1 H), 7.38 (Her, 9U-9.60 Hz, 1 H ), 7.06 (1, 9U-8.21 Hz, 1 H), 6.98 (a, 9U-2.27 Hz, 1 H), 6.81 (d4, 9U-5.81, 2, 27 Hz, 1 H), 6.53 (5, 1 H), 3.85 (5.2 H), 2.61 (5, Z H), 2.11 (aaa, U-7.01, 3 .35, 3.03 Hz, 1 N), 0.34 - 0.49 (t, 4 N).

Example 68 68-А. 5-(6-Benzyloxymethylpyrimidin-4-yloxy)-2,3-dihydro-1H-indole.

SSO

N

O0-

Triethylsilane (4 mL, 24.7 mmol) and TFA (6 mL) were added to 5-(6-benzyloxymethylpyrimidin-4-yloxy)-1H-indole (0.22 g, 0.682 mmol) in 6 mL of acetonitrile and stirred at RT during the night

The reaction mixture is concentrated and an oil is obtained, which is dissolved in EAs and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, dried and concentrated to give crude 5-(6-benzyloxymethylpyrimidin-4-yloxy)-2,3-dihydro-1H-indole. MS (ER) t/2 334.2 (М-А1). 68-88. (3-Trifluoromethylphenyl)-amide of 5-(6b-benzyloxymethylpyrimidin-4-yloxy)-2,3-dihydroindole-1-carboxylic acid.

In water, 5-(6-Benzyloxymethylpyrimidin-4-yloxy)-2,3-dihydro-1H-indole (0.17 g, 0.509 mmol) is dissolved in

THF (3 mL) and cooled to 0 °C and 1-isocyanato-3-trifluoromethylbenzene (80 µL, 0.571 mmol) was added and the reaction mixture was heated to RT overnight. The reaction mixture was concentrated to give an oil which was absorbed on silica gel and purified by with the help of KFC (0-50 95

EtOAc/heptane) and obtain the desired compound. MS (IER) t/2 521.1 (M--1). 68-60. 5-(6-hydroxymethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide.

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(3-Trifluoromethylphenyl)-amide 5-(6-benzyloxymethylpyrimidin-4-yloxy)-2,3-dihydroindole-1-carboxylic acid (4.11 g, 7.90 mmol) is dissolved in TFC (100 ml) and heated at 60 °C overnight. The reaction mixture was cooled to RT and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated, dried and concentrated and the residue was absorbed on silica gel and purified by KFC (0-100 95 ethyl acetate: heptane) and obtain the desired compound. MS (IR) t/2 431.1 (M--1). 68-0. 6-(1-(3-Trifluoromethylphenylcarbamoyl)-2,3-dihydro-1H-indole- 5-yloxy|-pyrimidin-4-ylmethyl ether of methanesulfonic acid (3-trifluoromethylphenyl)-amide 5-(6-hydroxymethylpyrimidin-4-yloxy)-2 3-Dihydroindole-1-carboxylic acid (0.1001, 0.232 mmol) was dissolved in THF (6 mL) and TEA (0.18 mL, 1.29 mmol) was added, followed by methanesulfonyl chloride (0.028 mL, 0.361 mmol). for 15 minutes and then subjected to distribution among ets lactate and a saturated aqueous solution of sodium chloride. The layers are separated and the organic layer is additionally washed with water. The organic layer is then separated, dried and concentrated to obtain the desired compound. MS (ER) t/2 510.0 (t--1). 68-E. 5-(6b-methylaminomethylpyrimidin-4-yloxy)-2,3-dihydroindole-1-carboxylic acid (3-trifluoromethylphenyl)-amide.

Su

FO about

6-(1-(3-Trifluoromethylphenylcarbamoyl)-2,3-dihydro-1H-indol-5-yloxy|-pyrimidin-4-ylmethyl ether of methanesulfonic acid (0.1331 g, 0.261 mmol) in 10 ml of THF is added to a 40 95 solution of methylamine in water (0.4 ml, 4.58 mmol) and stirred at room temperature overnight.

The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer is separated, dried and concentrated and an oil is obtained, which is dissolved in ether, cooled to 0 "C and treated with 0.3 ml of 1N HCl in ether to obtain a salt of HCl (3-trifluoromethylphenyl)-amide 5-( 6b-methylamino-methylpyrimidin-4-yloxy)-2,3-dihydroindole-1-carboxylic acid. MS (IR) t/2 444.1 (t-a1); "H NMR (400 MHz, DMSO-dv) b parts/million 9.26 (Bg. 5., 1 H), 8.93 (5, 1 H), 8.85 (5, 1 H), 8.05 (5, 1 H), 7.94 (a, 9U-8.84 Hz, 2 H), 7.54 (I, 9U-8.08 Hz, 1 H), 7.36 (y, 9U-7.58 Hz, 1 H), 7, 21 (5, 1 H), 7.11 (y, y-2.53 Hz, 1 H), 6.98 (da, 9U-8.72, 2.40 Hz, 1 H), 4.31 ( Bg. 5., 2 H) 4.23 (I, 9U-8.59 Hz, 2 H), 3.23 (I, U-8.46 Hz, 2 H), 2.64 (Bri. 5. , Z H).

The following compounds are obtained by a similar method. with. MS (ER)

ST osvuyuennennnkh 00|00nyaesyumo r (DMSO-dv) 6 parts/million 8.93

M. 0 (5, 1 N), 8.85 (5, 1 N), 8.05 (5, 7 IF, 1 N), 7.88 - 7.96 (t, 2 N), 7, 54

M. 2 M SE (i, U-8.08 Hz, 1 H), 7.31 - 7.38 re Z (t, 2 H), 7.11 (a, 9-1.77 Hz, 1

H), 6.99 (ad, 9U-8.72, 2.15 Hz, 1 bV-E I op H), 447 (be. 8., 2 H) 4.23 (1, 500.0 3- 8.59 Hz, 2 H), 3.86 (bBg. 5., C (3-trifluoromethylphenyl)-amide hydrochloride 5-(6- H) 3.78 (a, 95.05 Hz, 1 H), morpholine- 4-ylmethylpyrimidin-4-yloxy)-2,3- | 9.931 - 3.40 (t, 2 H), 3.24 (t, 4 dihydroindole-1-carboxylic acid H) (DMSO-dv) 6 parts/million 8.93

M. ,0 (5, 1 H), 8.82 (5, 1 H), 8.15 (ri. "still IF; 8., 2 H), 8.05 (in, 1 H), 7, 88 -

M. M C 7.95 (t, 2 H), 7.54 (I, 9-7.96 in 3 Hz, 1 H), 7.36 (a, U-8.08 Hz, 1 68-a MH o! and H), 7.18 (5.1 H), 7.10 (a, 430.0 2 3-2.53 Hz, 1 H), 6.97 (aa, (Z-trifluoromethylphenyl) - amide hydrochloride 5-(6-| 9U-8,59, 2,53 Hz, 1 H), 4,15-aminomethyl-pyrimidin-4-yloxy)-2,3-dihydro- | 4.26 (t, 4 H), 3.23 (Her, 9-8.59 indole-1-carboxylic acid Hz, 2 H).

M Ge) (DMSO-dv) b frequency/million 9.45

Ce IF, (VG. 8., 1 H), 8.93 (in, 1 H), 8.86

M. 2 M C (a, 9U-1.01 Gu, 1 H), 8.05 (5, 1

XM with IN), 7.88 - 8.00 (t, 2 H), 7.54 o y (i, 9U-7.83 Hz, 1 H), 7.36 (y, 68-H 9 -k uU-7.83 Hz, 1 N), 7.25 (5.1 N), 5141

H 7.11 (a, 9-2.53 Hz, 1 H), 6.98 (3-trifluoromethylphenyl)-amide hydrochloride 5-16-| (09, 9U-8.59, 2.53 Hz, 1 N), 4.34

IKtetrahydropyran-4-ylamino)-methyl/|-pyrimidine-| - 4.39 (t, 2 H), 3.93 (y, 4-yloxy)-2,3-dihydroindole-1-carboxylic acid y-11.37 Hz, 2 H), 3.19 - 3.32 acid (t, 4 H), 1.99 (a, U-1.52 Hz, 2

BZZVA--- Blysheite - 2 H), 1.04 (4, y-6.06 Hz, C H). (DMSO-dv) 6 ppm 10.71 fe, (bg. 5., 1 N), 9.00 (bg. v., 1 N), ee If, 8.85 (5, 1 N) , 8.07 (eg. 5., 1 M),

M. 22 M CE 7.93 (I, 9-7.45 Gu, 1 H), 7.48 - rya Z 7.58 (t, 1 H), 7.43 (bBg. 5., 1 H) , 7.35 (a, 9-6.57 Gu, 1 H), 7.11

Z on (og. 5., 1 H), 6.99 (4.9-8.08 Hz, 7750 1 H), 4.41 (ri. 5.2) 420 - (3-trifluoromethylphenyl)-amide hydrochloride 5-( 6- | 4.30 (t, 2 H), 3.29 - 3.48 (t, C piperidin-1-ylmethylpyrimidin-4-yloxy)-2,3- | H), 3.23 (Bi. 5 ., 2 N) 9.00 (ru. of dihydroindole-1-carboxylic acid 5" 2 tvo (g. 5., 4 N) 1.36 g. 8. m. o (DMSO-dv) b parts/million 10.35 ge (Lg. 5., 1 H), 8.94 (5, 1 H), 8.87 these r IF, (9, 9-1.01 Hz, 1 H), 8.05 (5 , 1

M CE, H), 7.88 - 7.96 (t, 2 H), 7.54 r Khm (and 9-8.08 Hz, 1 H), 7.32 - 7.37 68-9 M o n (t, 1 N), 7.12 (a, U-2.27 Hz, 1 472.0

C H), 6.99 (yes, Y-8.72, 2.65 Hz, 1 and 4 H), 4.42 (rg. 5., 4 H), 4.23 (Y, (3-trifluoromethylphenyl ) -amide hydrochloride 5-16- 9-8.72 HC, 2 H), 3.23 (i, 9-8.59

Ketylmethylamino)-methyl| -pyrimidin-4-yloxy- Hz, 2 H), 2.78 (5, C H), 1.27 (i, 2,3-dihydroindole-1-carboxylic acid U-7.20 Hz, C H) o ) (DMSO-dv) 6 ppm 8.90 pe IF, (4.9-19.71 Hz, 2 N), 8.05 (5.1

M. M SE H), 7.88 - 7.96 (t, 2 H), 7.54 ry Hm with (5 9-7.83 Hz, 1 H), 7.32 - 7.37 (t , 2 H), 7.12 (a, 9-2.53 Hz, 1 b8-K S. on H), 6.99 (ad, y-8.84, 2.53 Hz, 1.76

H), 4.47 (4.9-3.79 Hz, 2 H), (3-trifluoromethylphenyl)-amide hydrochloride 5-(6-| 4.23 (i, 9U-8.59 Hz, 2 H), 3,14 - diethylaminomethylpyrimidin-4-yloxy)-2,3- 3,26 (t, 6 H) 1,15-1,28 (t, 6 dihydroindole-1-carboxylic acid H). more (DMSO-dv) 6 parts/million 9.08 ha (B. v., 1 N), 8.94 (5, 1 N), 8.85

About IF; SU (in, 1 N), 8.05 (in, 1 N), 7.84-

SE. 8.00 (t, 2 H), 7.54 (i, 9-7.96

X-m Hz, 1 N), 7.29 - 7.42 (t, 1 N), 8-1 m on 7.11 (9, 9-2.53 Hz, 1 N), 6.99 516, 2

M 8 (449, U-8.59, 2.53 Hz, 1 H), 4.48 that (og. 5., 2 H), 4.23 (i, U-8.59 Hz, (Z- trifluoromethylphenyl)-amide hydrochloride 5-(6-|2 H), 3.53 (Bg. 5., 4 H), 3.17 - thiomorpholin-4-ylmethylpyrimidin-4-yloxy)-2,3- 3.29 ( t, C H), 2.99 (bu. 8., 2 N) dihydroindole-1-carboxylic acid 2.81 -2.90 (t, 1 N (DMSO-dv) 6 parts/million 9.23

MO (g. 8., 1 H), 8.94 (5, 1 H), 8.86 th IF; (9, 9-1.01 Hz, 1 N), 8.05 (5, 1

M. M SE H), 7.88 - 7.96 (t, 2 H), 7.54 uk with (5 9-7.96 HZ, 1 H), 7.36 (4, o U-7, 83 Hz, 1 N), 7.26 (5, 1 N), 68-M ry and background, kaz Hz) 0007729 (449, U-8.84, 2.53 Hz, 1 N), 4.32 ( 3-trifluoromethylphenyl)-amide hydrochloride 5-(6- | (5. 2 H), 4.23 (i, 9-8.59 Hz, 2 (isopropylaminomethyl)-pyrimidin-4-yloxy |-2,3- H) . 6 H)

(DMSO-dv) 6 ppm 9.34 "More (Bg. 5., 2 H) 8.93 (5, 1 H), 8.86 pe IF; (d, 9-1.01 Hz, 1 H), 8.05 (5, 1

M. Zh M S H), 7.B8 - 7.96 (t, 1 H), 7.54

Hm and tva t, v8-M MN on 9-1.01 Gu, 1 NU, 7.11 (4, 4980 3-2.53 Hz, 1 H), 6.98 (aa, "

C 3-8.59, 2.53 Hz, 1 H), 4.32 (Her, 9-5.94 Hz, 2 H), 4.23 (I, 9-8.59 (3-trifluoromethylphenyl) - amide hydrochloride 5-(6-| Hz, 2 H), 3.40-3.50 (t, 1 H), cyclopentyl-aminomethylpyrimidin-4-yloxy)- | 4

N) 1.49-1.58(t, 2 N (DMSO-dv) 6 parts/million 10.50

M. 0 (g. 5., 1 H), 8.94 (5, 1 H), 8.86 pe IF; (a, 9-1.01 Hz, 1 NU, 8.05 (5, 1

M. 2 M С H), 7.88 - 7.96 (t, 1 H), 7.54

Hmm! Methane, y t, ,; 7, ,; 58-0 t On Ch-1.01 Hz, 1 NU, 7.12 (9, 458.0 3-2.53 Hz, 1 H), 6.99 (aa, (Z-trifluoromethylphenyl)-amide hydrochloride 5- (6-|9-8.72, 2.65 HC, 1 H), 4.46 (5, dimethylamino-methylpyrimidin-4-yloxy)-2,3- |2 H), 4.23 (Her, 9 -8.72 Hz, 2 N), dihydroindole-1-carboxylic acid 3.23 (M, 5-8.46 Hz, 2 N), 2.83 5.6 N).

Example 69 69-А. 5-(2-Methylpyridin-4-yloxy)-1H-indole. 5. va;

M. 22 M

N

B-Hydroxyindole (133 mg, 3.76 mmol), 4-bromo-2-methylpyridine (711 mg, 4.13 mmol), and cesium carbonate (2.45 g, 7.52 mmol) were stirred in DMSO (3 mL) at 110 "C for 12 h. The mixture is then partitioned between DCM and water. The organic layer is separated, dried over anhydrous Mag5O4 and concentrated in vacuo. The residue is purified by KFC (from EtOAc/heptanes 2:8 to EIOAcC) and the desired compound is obtained . a, U-8.6 Hz, 1 N), 7.33 (a, U-3.0 Hz, 1 N), 7.29 (a, 9-2.3 Hz, 1 N), 6.86 (ad, uU-8,8, 2,3

Hz, 1 NN), 6.67 -6.77 (t, 2 N), 6.48 (y, 9-3.0 Hz, 1 N), 2.43 (5, C H). 69-8. 5-(2-Methylpyridin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide. about ES in oy

To a solution of 2,2,6,6-tetramethylpiperidine (0.27 ml, 1.08 mmol) in THF (5 ml) at -78 "С, pVygi (0.69 ml, 1.72 mmol, 2.5 M in hexanes). The solution was stirred for 15 min., then a solution of 5-(2-methylpyridin-4-yloxy)-1H-indole (242 mg, 1.08 mmol) in THF (2 mL) was added. The solution was then stirred for 30 min., then add 3-trifluoromethylphenylisocyanate (0.30 mL, 2.16 mmol).

The reaction mixture is stirred at room temperature for three hours. and then partitioned between EtOAc and a buffer solution with pH 7. The organic layer was dried over anhydrous

Ma5O" and concentrate. the residue is purified by KFC (10-70 95 EIOAc/heptane) and the desired compound is obtained. MS (IER) t/2 412.3 (M--1); "H NMR (400 MHz, meor) b frequency/million 8.38 (a, U-8.8 Hz, 1 H), 8.24 (a, 2-5.8 Hz, 1 H), 8, 08 (5, 1 H), 7.97 (a, 9-3.8 Hz, 1 H), 7.91 (a, 9-81 Hz, 1 H), 7.59 (i, 9U-8, 0 Hz, 1 H), 7.46 (a, 9-71 Hu, 1 H), 7.38 (a, 9-2.3 Hu, 1 H), 7.09 (aa, 2-8.8 , 2.3 Hz, 1 N), 6.80 (a, 9-2.3 Hz, 1 N), 6.72 - 6.78 (t, 2 N), 2.45 (in, C H) .

Example 70 70-А. 5-(Benzyloxy)-M-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide.

S, oh S

Willow;

M dk o nn

To a solution of 2,2,6,6-tetramethylpiperidine (8.38 ml, 49.3 mmol) in 200 ml of THF at -78 "С, 2.5 M of n-butyllithium (18 ml, 44.8 mmol) is added. Through 5-(benzyloxy)-1H-indole is added after 15 minutes. After another 15 minutes at -78 "C, 1-isocyanato-3-(trifluoromethyl)benzene is added dropwise and then stirred for 2 hours. at CT. The reaction mixture is concentrated and the resulting solid is triturated with heptane and collected by filtration to give the desired compound. MS (IER) t/ 411.1 (M-n1). 70-8. 70-8-1 5-Hydroxy-M-(3-"(trifluoromethyl)phenyl)-1H-indole-1-carboxamide and 70-8-2 5-hydroxy-M-(3-"(trifluoromethyl)phenyl) indoline-1-carboxamide.

E.S but what; but Z

Sl

M. U.

Engine 70-8-1 70-8v-2

A mixture of 5-(benzyloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide (6 g, 14.6 mmol) in 60 mL of EOH and 30 mL of EOAc with Ra/C (0.6 d) stir in a hydrogen atmosphere (1 atm.) at room temperature for 3.5 hours. An additional amount of Ra/C (0.6 g) was added and the mixture was stirred overnight. After filtration and concentration, the solid is triturated with DCM and heptane to obtain a mixture

B-hydroxy-M-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide and 5-hydroxy-M-(3-(trifluoromethyl)phenyl)indoline-1-carboxamide (6:4), which used at the next stage. 70-60. 5-(-2-Chloropyrimidine-4-yloxy)-M-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide

M o Ezb

SI from

M. U

M o nn

A mixture of 5-hydroxy-M-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide and 5-hydroxy-M-(3-(trifluoromethyl)phenyl)indoline-1-carboxamide (6:4) ( C d) at 0 "C is mixed with sodium hydroxide (0.45 g, 11.2 mmol) and 2,4-dichloropyrimidine (1.68 g, 11.2 mmol) in 50 ml of acetone and 50 ml of water and stirred for 1.5 h. Add additional sodium hydroxide (0.075 g, 1.88 mmol) and (0.279 g, 1.88 mmol). After additional stirring for 30 min, the reaction mixture is concentrated, diluted with EAs, washed with water and brine solution, then the organic layer is dried over sodium sulfate and concentrated.The residue is purified using

KFC (5-50 96 EOAcC in heptane) and obtain 5-(2-chloropyrimidin-4-yloxy)-M-(3-trifluoromethyl)phenyl)-1H-indole-1-carboxamide. "H NMR (400 MHz, SOSI") b frequency/million 8.45 (y, 9-5.7 Hz, 1 N), 8.24 (y, U-9.0 Hz, 1 N), 7.86 (5, 1 H), 7.78 (y, 9U-8.2 Hu, 1 H), 7.60 (a, 9-3.7 Hu, 1 H), 7.55 (I, 92-8.0 Hu , 1 N), 7.45 - 7.50 (t, 2

H), 7.42 (a, 9-21 Hu, 1 H), 7.15 (da, 2-8.9, 2.3 Hz, 1 H), 6.82 (a, 9U-5.7 Hz, 1 N), 6.73 (ai, 9-3.7, 0.6 Hz, 1

N). 70-0. 5-(-2-Cyanopyrimidin-4-yloxy)-M-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide.

M.O ES pes se If;

M. U

M o nn

A mixture of DMSO and HO (85:15), OAVSO (0.92 g, 8.148 mmol), then KSM (0.53 g, 8.148 mmol). The mixture is stirred at RT for 2.5 hours. and then diluted with EAs, washed with HgO and saline. The organic layer is dried over

Mag5O", filter and concentrate. The residue is purified using KFC (0-50 95 EIAs/heptane) and the desired compound is obtained. MS (IER) t/2 424.0 (M--1) 70-E. 5-(2-(Aminomethyl)pyrimidin-4-yloxy)-M-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide.

me o x ES ti ( | ; Z

M. 2 at the university

To a solution of / 5-(2-cyanopyrimidin-4-yloxy)-M-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide (1.49 g, 3.52 mmol) in 70 ml of THF at -78 "С, add OIVAY (1 M in DCM, 10.6 ml) dropwise and stir for 45 min. at -78 "С. The reaction is stopped with sodium-potassium tartrate solution and extracted with DCM (x3). The combined organic layers were washed with brine and dried over NaCl. After concentration, the residue is purified by HPLC (5-90 95 ACN in HgO with the addition of 0.1 95 TFA and the desired compound is obtained. MS (ER) t/: 428.1 (M--1); "H NMR (400 MHz ,

DMSO-dv) 6 ppm 10.41 (5, 1 N), 8.73 (y, 9-5.8 Hz, 1 N), 8.23 - 8.37 (t, C H), 8.17 (9, 9-3.8 Hz, 1 H), 8.10 (5, 1 H), 7.97 (a, 9U-8.3 Hz, 1 H), 7.65 (I, U-8.0 Hz, 1 N), 7.48 - 7.56 (t, 2 N), 7.18 (ai, U-8.8, 2.5 Hz, 1

H), 7.02 (9, 9-5.8 Hz, 1 H), 6.82 (y, U-3.8 Hz, 1 H), 4.12-4.20 (t, 2 H) .

Example 71 71-A. 5-(pyridin-4-ylmethoxy)-indole-1-carboxylic acid (3-fluoromethylphenyl)amide. about E.S

From the 5th to the M school

5-Hydroxyindole-1-carboxylic acid mono(3-trifluoromethylphenyl)-amide, compound of example 70-8-1 (150 mg, 0.47 mmol), pyridin-4-ylmethanol (51 mg, 0.47 mmol) and cyanomethylenetri-n-butylphosphorane (0.17 ml, 0.70 mmol) are heated in a sealed test tube at 100 "C for 15 h. The reaction mixture is then concentrated in vacuo and purified by KFC (10-90 EIOAc/heptane) to obtain the desired compound. MS (IR) t/2 412.3 (M--1); "H NMR (400 MHz, DMSO-dv) 6 ppm 10.26 (5.1 H), 8.58 ( a, 9-61 Hz, 2 H), 8.16 (a, 9-91 Hz, 1 H), 8.07 (5, 1 H), 8.03 (y, 9U-3.8 Gu, 1 H), 7.95 (a, U-8.8 Hz, 1 H), 7.63 (i, 9U-8.0 Hz, 1 H), 7.43 - 7.51 (t, C H) , 7.23 (9, 9-2.3 Hz, 1 H), 7.05 (da, 2-91, 2.5 Hz, 1 H), 6.71 (a, U-3.3

Hz, 1 N), 5.24 (5.2 N).

Example 72 72-А. (2-Isopropylaminopyridin-4-yl)-methanol. he

And I cha

Mom

A mixture of (2-bromopyridin-4-yl)-methanol (500 mg, 2.66 mmol), isopropylamine (0.45 mL, 5.32 mmol),

MasVy (790 mg, 7.98 mmol) and Ra(IVizR)2 (136 mg, 0.26 mmol) in 1,4-dioxane (5 ml) are heated in a microwave reactor at 110 "C for 45 min. The reaction mixture is diluted by using

DCM (50 ml) and washed with a saturated aqueous solution of MNACI. The organic layer was separated, dried over anhydrous Mag50O54 and concentrated in vacuo to give the desired compound, which was used without further purification. MS (ER) t/2 167.1 (M-n1). 72-8. 5-(2-isopropylaminopyridin-4-ylmethoxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide. about EU

With o and M

A (C) Hmm

M M o nn

N

5-Hydroxyindole-1-carboxylic acid (3-trifluoromethylphenyl)-amide (100 mg, 0.31 mmol), (2-isopropylaminopyridin-4-yl)-methanol (63 mg, 0.37 mmol) and cyanomethylenetri-n -butylphosphorane (112 mg, 0.46 mmol) is heated in a sealed test tube at 90 "C for 2 h. Then the solution is concentrated in a vacuum and the residue is processed using semi-preparative HPLC (C18; 10-100 95 ACN/NgO with the addition of 0.1 95 TFA) and obtain the desired compound. MS (IER) t/g 469.2 (Ma1); "H

NMR (400 MHz, DMSO-av) 6 ppm 10.26 (5, 1 N), 8.14 (a, 9-91 Hz, 1 N), 8.07 (5, 1 N), 8 ,02 (y, 9U-3.5

Hz, 1 N), 7.90 - 7.98 (t, 2 N), 7.63 (i, 9-8.0 Gu, 1 N), 7.48 (a, 9U-8.3 Hz, 1 N), 7.19 (a, 9U-2.5 Hz, 1 N), 7.00

(ad, 9U-9.0, 2.7 Hz, 1 N), 6.70 (a, 9-38 Hz, 1 N), 6.45 - 6.52 (t, 2 N), 6.35 (0, 9-7.6 Hz, 1 N), 5.03 (5.2 N), 3.90 - 4.03 (t, 1 N), 1.12 (a, 9-6.6 Hz , 6 H).

Example 73 73-А. 5-(2-Chloropyrimidine-4-yloxy)-1H-indole. no) shodo;

M. M

N

2,4-dichloropyrimidine (5.6 g, 37.6 mmol) was added to a solution of 1H-indole-5-ol (5.0 g, 37.6 mmol) in 40 ml of ACN, and the solution was cooled to 0 °C and DBU (5.71 mL, 37.6 mmol) is added dropwise.

The reaction mixture is allowed to warm to room temperature and stirred for 2 h. and then concentrate.

The residue is transferred to EtOAc, washed with H2O (x2), brine, and the organic layer is dried over Mag2505. After concentration, the resulting solid was triturated with DCM and heptane and collected by filtration to give the desired compound. "H NMR (400 MHz, CO»2sSig2) b freq./million 8.29 - 8.50 (t, 2 H), 7.35 - 7.49 (t, 2 H), 7.29 (I, 9-2.9 Hz, 1 H), 6.97 (aa, U-8.6, 2.3 Hz, 1 H), 6.70 (a, 9U-5.8 Hu, 1 H), 6 .53 - 6.60 (t, 1 H). 73-8. 5-(2-Vinylpyrimidin-4-yloxy)-1H-indole.

We h

M. M

N

A mixture of 5-(2-chloropyrimidin-4-yloxy)-1H-indole (1 g, 4.082 mmol), tributyl(vinyl)stannane (1.79 mL, 6.12 mmol) and RA(PP3)4" (0.377 g , 0.327 mmol) in 1,4-dioxane (10 ml) and toluene (10 ml) is heated in a microwave reactor at 140 "C for 30 minutes. Then the reaction mixture is diluted with EOAc, washed with HgO (x3), saline and the organic layer is dried over Mag505. After concentration, the residue is purified with KFC (0-50 95 EIAs/heptane) and the desired compound is obtained. MS (ER) t/2 238.0 (M.n1). 73-60. 4- (2-(4-(1H-Indol-5-yloxy)pyrimidin-2-yl)ethylmorpholine. t-th M.,0 o A If;

X / M. 2 M

N

A mixture of 5-(2-vinylpyrimidin-4-yloxy)-1H-indole (0.45 g, 1.90 mmol), morpholine (0.33 mL, 3.80 mmol), and acetic acid (0.20 mL, 3 .42 mmol) in 15 ml of EN is heated in a microwave reactor at 120 "С for 30 min. Then the solution is concentrated and the residue is transferred to EAs, washed with H2O (x2), saturated aqueous solution of MnSOOz, brine and the organic layer is dried over Mg5O4 After concentration, the desired compound is obtained and it is used in the next stage without additional purification. MS (ER) t/l 325.1 (M.n1). 73-0. 5-(2--2-Morpholinoethyl)pyrimidine-4- yloxy)-M-(3-"trifluoromethyl)-phenyl)-1H-indole-1-carboxamide. o M o EzC

She

OO So Z

M. 22 in the

To a mixture of 2,2,6,6-tetramethylpiperidine (TMP, 0.18 ml, 1.05 mmol) and THF (12 ml) at -78 C is added p-VIII and (0.42 ml, 1 M in hexane) . In 10 minutes. add drop by drop a solution (4-(2-(4-(1 H-indol-

B-yloxy)pyrimidin-2-yl)ethyl morpholine in 5 ml of THF. The solution is stirred at -78 "C for 30 min. and then 1-isocyanato-3-(trifluoromethyl/benzene) is added dropwise and stirring is continued at -78 "C for another 1 h. The reaction is stopped with Meon and then concentrated. The residue is transferred in EtOAc, washed with H2O (x2), brine, and the organic layer was dried over Mag250" 5. After concentration, the residue was purified by KFC (0-595 Meon/dxM) and then by semi-preparative HPLC (20-60 95 SNZSM in HO with the addition of 0.1 95 MNAOH and obtain the desired compound. MS (IR) t/2 512.2 (M-41); "H NMR (400 MHz,

DMSO-dv) 6 ppm 10.38 (bBg. 5., 1 N), 8.56 (a, 9U-5.8 Hz, 1 N), 8.29 (a, U-9.1 Hz, 1 N), 8.13 (a, 9-3.8 Hz, 1 N), 8.09 (5, 1 N), 7.97 (y, 9-91 Hz, 1 N), 7, 64 (I, 2U-8.0 Hz, 1 H), 7.44 - 7.53 (t, 2 H), 7.14 (ad, 9-9.0, 2.4

Hu, 1 H), 6.85 (a, 9U-5.8 Hu, 1 H), 6.78 - 6.82 (t, 1 H), 3.46 - 3.52 (t, 4 H) , 2.85 (I, U-7.3 Hz, 2 N), 2.64 (Her, 9-7.3 Hz, 2 N), 2.27 - 2.37 (t, 4 N).

The following compounds are obtained by a similar method. 73-B. 5-(2-(2-(Isopropylamino)ethyl)pyrimidin-4-yloxy)-M-(3-trifluoromethyl)phenyl)-1H-indol-1-

carboxamide - more shko; taking a dose

N. M. M

H-m o nn

MS (ER) t/2 484.3 (M--1); "H NMR (400 MHz, DMSO-av) b frequency/million 8.56 (a, U-5.8 Hz, 1 N), 8.30 (a, u3-8.8 Hz, 1 N), 8.13 (a, U-3.8 Hz, 1 H), 8.09 (5, 1 H), 7.97 (a, 9-86 Hz, 1 H), 7.64 (I, 2- 81 Hz, 1 H), 7.45 - 7.53 (t, 2 H), 7.15 (aa, 2-88, 2.3 Hz, 1 H), 6.87 (a, U-5, 8 Hz, 1 N), 6.79 (a, U-3.5 Hz, 1 N), 2.80 (5.4 N), 2.55 - 2.68 (t, 1 N), 0, 85 (y, 9-6.1 Hz, 6 N).

Example 74 7A4-A. (3-Trifluoromethylphenyl)-amide 5-(2-(5-oxo-4,5-dihydro-|1,3,4|oxadiazol-2-yl)-pyridin-4-yloxy|-indole-1-carboxylic acid o EzS ia;

M o m o nn University (in)

EM (0 .09 mL), DMF (2 drops) and oxalyl chloride (0.17 mL, 0.340 mmol, 2.0 M DCM). After 0.5 hours add tert-butyl carbazate (0.045 g, 0.340 mmol). After 1.5 hours the solution is diluted with DCM (10 ml) and then washed with pH 7 buffer (15 ml). The organic layer is then dried (Mag25054), filtered and concentrated. The residue is purified by KFC (30-60 96 E(Ac/heptane)) and M'-14-(1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyridine-2-carbonyl)-hydrazinecarbonate is obtained acid tert-butyl ether MS (ER) t/2 484.3 (M--1).

Then M'-4-P1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyridine-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ether (0.105 g, 0.189 mmol) is transferred to DCM (2 ml) and processed

TFC (0.5 ml). After 2 hours the solution is concentrated in a vacuum. The resulting residue was then taken up in THF (3 mL) and EiBzZM (0.079 mL) and carbonyldiimidazole (0.046 g, 0.283 mmol) were added. After 0.5 hours the solution is concentrated and the residue is purified using semi-preparative HPLC (20-100 95 ACN/HgO with the addition of 0.1 95 MNAOH) and the desired compound is obtained. MS (IER) t/2 484.3 (M-n1).

Example 75 75-А. 1-6-11-(4-Fluoro-33-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyrimidin-4-ylmethyl)-piperidine-3-carboxylic acid.

E.S

Mao Z E co

May 22 at the United Nations

To a solution of ethyl ether of 1-16-1-(4-fluoro-3-trifluoromethylphenyl-carbamoyl)-1H-indol-5-yloxy|pyrimidin-4-ylmethyl)-piperidine-3-carboxylic acid (obtained by a method similar to described in example 19) (0.32 g, 0.55 mmol) in THF (5.5 mL) was added GiOH (0.92 g, 22 mmol) in HgO (8.75 mL) and the reaction mixture was stirred overnight. The reaction mixture is acidified to pH 4 with 1 n.

NSI and then extracted with EOAc (3x). Then the compound is purified using semi-preparative HPLC (12-48 95 СНаСМ/Н2О with the addition of 0.195 TFC) and the desired compound is obtained. MS (IER) t/2 558.9 (M.n1).

Example 76 76-А. 5-(6-(Benzyloxymethyl)pyrimidin-4-yloxy)-N-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide.

E.S

Ge) Z

Su S

What about

M o o nn

To a solution of TMP (1.15 ml, 6.757 mmol) in 30 ml of THF at -78 "C, p-Vii (1.15 ml, 2.88 mmol) is added. After 10 minutes, a solution of 5-(6- (benzyloxymethyl)pyrimidin-4-yloxy)-1H-indole (0.868 g, 2.62 mmol) in 5 ml of THF and stirred at -78 "С. Reaction 2: Triphosgene (0.931 g, 3.14 mmol) is added to a solution of 3-methoxy-5-(trifluoromethyl)aniline (0.6 g, 3.14 mmol) in 20 ml of DHE at 0 "С, then TEA (1 .74 mL, 12.6 mmol). The solution is allowed to warm to room temperature and stirred for 45 min. Then reaction mixture 2 at -78 "C is added dropwise to reaction mixture 1 and stirred for 2 h. The reaction is then quenched with Meon and concentrated. The residue is transferred to EtOAc, washed with H2O (x2), brine, and the organic layer is dried over

Mag5O»:. After concentration, the residue is purified by KFC (5-65 95 EOAc/heptane) and the desired compound is obtained, which is used in the next step without treatment. MS (IER) t/: 549.1 (M-y1). 76-8. 5-(6-"Hydroxymethyl)pyrimidin-4-yloxy)-N-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide.

IF)

IF) Z shi;

M. 2 M o

Mm and; he he 5-(6-"Benzyloxymethyl)pyrimidin-4-yloxy)-M-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide (0.94 g, 1, 72 mmol) at 60 "C for 24 hours is treated with TFA (9.5 ml).

After concentration, the residue is transferred to EIAs, washed with saturated Mansoz solution (xg), saline solution, and the organic layer is dried over Mag2505. After concentration, the residue is purified by KFC (20-90 95 EIOAc/heptane) and then semi-preparative HPLC (20-60 95 CH3CM in HO with the addition of 0.1 95 MNAOH) and the desired compound is obtained. MS (IER) t/2 459.0 (M--1); "H NMR (400 MHz,

DMSO-dv) b frequency/million 10.35 (Bg. 5., 1 N), 8.65 (5, 1 N), 8.31 (a, 9-91 Hz, 1 N), 8.12 (a, U-3.5 Hz, 1 H), 7.69 (5, 1 H), 7.60 (i, 9-1.9 Gu, 1 H), 7.50 (a, 9-2 ,3 Gu, 1 H), 7.15 (aa, U-8.8, 2.3 Hz, 1 H), 6.95 - 7.06 (t, 2 H), 6.60 (a, 9 -3.5 Hz, 1 N), 5.61 (1, 9-5.7 Gu, 1 N), 4.52 (y, 2-5.8 Hz, 2 N), 3.86 (5, With N). 76-06. 5-(6-Formylpyrimidin-4-yloxy)-N-(3-methoxy-5-(trifluoromethyl)-phenyl)-1H-indole-1-carboxamide.

E.S

Go) With in; Oh El Yak

M c) N o nn

To a solution of /5-(6-(hydroxymethyl)pyrimidin-4-yloxy)-M-(3-methoxy-5-trifluoromethyl)phenyl)-1H-indole-1-carboxamide (0.260 g, 0.568 mmol) RDM (0.265 g, 0.624 mmol) is added to DCM (8 ml) at 0 "C. Then the mixture is allowed to heat up to room temperature and stirred for 2 hours. and then diluted with EAs and washed with an aqueous solution of ManHCO3/Mag252Ox4. Then the organic layer is dried and concentrated and the residue is purified by KFC (10-60 96 EIAs/heptane) to obtain the desired compound. MS (IER) t/2 457.0 (M.n1). 76-0. M-(3-Methoxy-5-(trifluoromethyl)phenyl)-5-(6-((methylamino)methyl)-pyrimidin-4-yloxy)-1H-indole-1-carboxamide.

E.S o) Z

Fshf; that ec

M

MN about nN

To a solution of /5-(6-formylpyrimidin-4-yloxy)-M-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide (0.219 g, 0.479 mmol) in 3 ml of DCM is added 2 M methylamine in THF (0.72 mL, 1.43 mmol) and stirred at RT for 45 min. Then, Ma(OAc)zVN (0.406 g, 1.92 mmol) was added, followed by acetic acid (0.14 mL) and the mixture was stirred at RT for 1.5 h. and then diluted with EtOAc, washed with a saturated aqueous solution of ManHsCO3 (x2) and saline.

The organic layer is dried over Mag5O:. After concentration, the residue is purified using semi-preparative HPLC (C-phenyl; 20-60 96 ACN/H2gO with the addition of 0.195 MNAOH) and the desired compound is obtained. MS (IER) t/2 472.0 (M--1); "H NMR (400 MHz, DMSO-dv) b frequency/million 10.34 (Bg. 5., 1 H), 8.65 (a, 9-1.0 Hz, 1 H), 8.29 ( a, 9-9.1 Hu, 1 H), 8.12 (a, 9-3.5 Hu, 1 H), 7.70 (5, 1 H), 7.60 (5, 1 H), 7.49 (a, y-2.3 Hz, 1 N), 7.15 (aa, 2-8.8, 2.5 Hz, 1 N), 7.01 - 7.06 (t, 2 N ), 6.80 (a, 9-3.8 Hz, 1 H), 3.86 (5, C H), 3.71 (5, 2 H), 2.29 (5, C H).

The following compounds are obtained by a similar method. 76-E. M-(4-Methoxy-3-trifluoromethyl)phenyl)-5-(6-((methylamino)methyl)-pyrimidin-4-yloxy)-1H-indole-1-carboxamide.

E.S

WITH

Mu U

M

MN about nn

MS (IER) t/2 472.0 (M--1); "H NMR (400 MHz, DMSO-av) 5 ppm 10.18 (Bg. 5., 1 H), 8.65 (a, 9U-1.0

Hu, 1 N), 8.28 (a, U-8.8 Hz, 1 N), 8.10 (a, U-3.5 Hz, 1 N), 7.95 (a, 9-2, 5 Hz, 1 N), 7.90 (aa, 9U-9.0, 2.7 Hz, 1

H), 7.48 (a, 20-2.5 Hz, 1 H), 7.33 (a, 2-91 Hz, 1 H), 7.13 (da, U-9.0, 2.4 Hz, 1 H), 7.03 (a, U-0.8 Hz, 1 H), 6.79 (a, 9-3.5 Hz, 1 H), 3.90 (5, C H), 3.70 (5, 2 H), 2.29 (5, C H). 76-B. 5-(6-4((1H-Tetrazol-5-yl)umethylamino)methyl)pyrimidin-4-yloxy)-M-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide .

EC

Ge) Z

M. U

M

MN o nshka

M,

Name of

MAM

MS (ER) t/2 528.1 (M--1); "H NMR (400 MHz, DMSO-av) 5 ppm 10.41 (5, 1 N), 8.84 (5, 1 N), 8.31 (a, 9-91 Hz, 1 N) , 8.09 - 8.15 (t, 2 H), 7.95 - 8.05 (t, 1 H), 7.58 (Y, U-9.9 Hu, 1 H), 7.51 ( a, 9-2.3 Hz, 1 H), 7.23 (5, 1 H), 7.16 (aa, 9-8.8, 2.3 Hz, 1 H), 6.83 (a, 9U-3.8 Gu, 1 H), 4.56 - 4.67 (t, 2 H), 4.39 -- 4.49 (t, 2

N).

Example 77 77-А. (3-Trifluoromethylphenyl)-amide (5)-5-(16-(1-hydroxyethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid.

EC o) With vv;

M. 2 U

M on on

A solution of methyl magnesium bromide (3 M in ether, 20 ml) was added to a solution of 5-(6-formylpyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide (5.0 g, 11.7 mmol) in THFf (400 ml) at 0 "С.

The mixture is stirred at this temperature for 3 hours, then the reaction is stopped with a saturated aqueous solution of MNACI. The product was extracted with EOAc (3x40 mL) and the combined organic layers were washed with brine, dried over anhydrous NaCl, filtered and concentrated.

The residue is purified using semi-preparative HPLC (C18; 30-100 95 ACN/H2O with the addition of 0.1 95 TFA) and the desired compound is obtained in the form of a racemate. MS (ER) t/2 441.1 (M-1); "H NMR (400

MHz, meor) b frequency/million 8.62 (5, 1 N), 8.36 (y, U-8.84 Gu, 1 N), 8.06 (5, 1 N), 7.95 ( a, 9-3.79 Hz, 1 H), 7.90 (a, U-8.08 Hz, 1 H), 7.58 (I, 9U-7.83 Hz, 1 H), 7.43 (a, 9-2.27 Hz, 2 H), 7.12 (da, 9-8.97, 2.40 Hz, 1 H), 7.09 (5, 1 H), 6.75 (0 , U-3.79 Hz, 1 H), 4.75 (a, 9-6.57 Gu, 1 H), 1.45 (a, 9U-6.57 Hz, C H).

The racemate of the compound of example 77-A is purified by chiral HPLC (column SpPigaIrac 00;

NRH with the addition of 2095 MeonN, flow rate: 3.2 ml/min.) and receive two corresponding enantiomers 77-A-1 (Be 3.33 min.) and 77-A-2 (NN: 4.65 min.) . 77-A-1.. (3-Trifluoromethylphenyl)-amide of 5-I(6-(1-hydroxyethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid. MS (ER) t/2 443.0 (M--1); "H NMR (400 MHz, mMeob) 5 ppm 8.61 (a, 9U-1.01 Hz, 1 H), 8.35 (a, U-9.09 Hz , 1 H), 8.06 (5, 1 H), 7.94 (y, U-3.54 Hz, 1 H), 7.89 (a, 9-8.08 Hz, 1 H), 7 ... 7.11 (aa, 2U-8.97, 2.40 Hz, 1 H), 7.09 (5, 1 H), 6.74 (a, 9-3.54 Hz, 1 H), 4, 76 (a, Y-6.65 Hz, 1 H), 1.45 (a, 2-6.57 Hz, C H). 77-A-2.. (3-Trifluoromethylphenyl)-amide 5-(6 -(1-hydroxyethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid.

MS (ER) t/2 443.0 (M--1); "H NMR (400 MHz, Meor) b frequency/million 8.62 (5.1 H), 8.36 (a, 9U-9.09 Hz, 1

H), 8.06 (5, 1 H), 7.94 (a, 9-3.79 Hz, 1 H), 7.89 (a, 9-7.83 Hz, 1 H), 7.56 (I, 9U-7.96 Hu, 1 H), 7.44 (a, O-7.83

Hz, 1 H), 7.42 (a, 90-2.27 Hz, 1 H), 7.11 (aa, U-8.97, 2.40 Hz, 1 H), 7.09 (5, 1 H), 6.74 (a, 2-3.79 Hz, 1 H), 4.76 (a, 9-6.82 Hu, 1 H), 1.45 (a, 9-6.57 Hu , Z H).

Example 78 (3-Trifluoromethylphenyl)-amide of 5-(b-formylpyrimidin-4-yloxy)-indole-1-carboxylic acid.

She EC

Su

Mi u o (in); N

RDM (337 mg, 0.795 mmol) was added to a suspension of 5-(6-hydroxymethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide (310 mg, 0.724 mmol) in DCM (10 mL).

The reaction mixture is stirred at CT until the end of the reaction according to LCMS (approximately 1 hour).

The reaction is stopped with a saturated aqueous solution of MansoO»3 and extracted with EtOAc (3x10 ml). The combined organic layers are then washed with brine, dried (Mag50O54), filtered and concentrated. The crude residue is purified by KFC (0-40 95 EtOAc/heptane) and the desired compound is obtained. MS (IER) t/2 443.1 (M-1); "H NMR (400 MHz, Meor) 5 parts/million 8.84 (y, 9-1.01 Hz, 1 H), 8.36 (a, Y-9.09 Hz, 1 H), 8, 06 (5, 1 N), 7.96 (a, U-3.79 Hz, 1 N), 7.89 (5, 1 N), 7.55 - 7.60 (t, 1 N), 7 .45 (5, 1 N), 7.40 (9, 9-1.01 Hz, 2 N), 7.44 (a, 2-2.53 Hz, 1 N), 7.13 (da, 9U -8.97, 2.40 Hz, 1 H), 6.76 (a, 9-3.79 Hz, 1 H), 2.66 (5, C H).

Example 79 79-А. 5-(6-(1-methylaminoethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide.

Es o) From the seam;

M. u

MN on

To a solution of 5-(6-formylpyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide (200 mg, 0.45 mmol) in Meon (10 mL) was added acetic acid (0.1 mL ), then methylamine in

Meon (0.25 ml). The mixture is stirred for 10 min., then MasM)VHz (86 mg, 1.35 mmol) is added. The mixture is stirred overnight and then the MeOH is removed. The residue is subjected to partitioning between a saturated aqueous solution of MnSSOO and EIHUAs. The aqueous layer was further extracted with EOAc (2x30 ml) and the combined organic layers were washed with brine, dried over anhydrous NaCl, filtered and concentrated. The residue is purified using semi-preparative HPLC (C18; 10-100 96 ACN/H2O with the addition of 0.1 9o TFA) and the desired compound is obtained. MS (IER) t/2 456.1 (M--1); "H NMR (400 MHz, Meor) 5 parts/million 8.66 (a, U-1.01 Hz, 1 H), 8.35 (a, 9-9.09 Hz, 1 H), 8, 06 (5, 1 H), 7.94 (a, 9U-3.54 Hz, 1 H), 7.89 (j, 9U-8.34 Hz, 1 H), 7.56 (I, U- 7.96 Hz, 1 H), 7.44 (a, y0-8.08 Hz, 1 H), 7.42 (a, U-2.53 Hz, 1 H), 7.11 (ad, U -8.97, 2.40 Hz, 1 N), 7.00 (5, 1 N), 6.74 (a, 9-3.79 Hz, 1 N), 3.71 (a, 9-6 .82 Hz, 1 H), 2.28 (5, C H), 1.36 (y, 9-6.82 Hz, C H).

The following compounds are obtained by a similar method. 79-А B. (3-Trifluoromethylphenyl)-amide of 5-(6-(1-cyclopropylaminoethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid.

E.S

Ge) Z

Su

M. 22 u

MN on

MS (ER) t/2 482.1 (M--1); "H NMR (400 MHz, Meor) b frequency/million 8.66 (5.1 H), 8.34 (a, 2-9.09 Hz, 1

H), 8.05 (5, 1 H), 7.93 (j, 9-3.79 Hz, 1 H), 7.89 (a, 9-8.08 Hz, 1 H), 7.55 (I, 9U-8.08 Hz, 1 N), 7.40 (а, 9-2.27

Hu, 1 H), 7.43 (a, U-7.83 Hu, 1 H), 7.09 (ad, U-8.97, 2.40 Hz, 1 H), 7.02 (5, 1 H), 6.73 (a, 9-3.79 Hz, 1 H), 3.89 (a, 9-6.82 Hz, 1 H), 1.98 (aa, 9U-10.48, 2.91 Hu, 1 H), 1.35 (y, U-6.82 Hu, Z H), 0.34 (NK, U-4.01, 1.93 Hz, 4 H).

The racemate is separated by chiral HPLC (SpPigairak AB column; heptane/BgyunH 1-1), flow rate: 14 ml/min.) and two corresponding enantiomers 79-А В-1 (В, 7.10 min.) and 79 are obtained -А B-2 (B: 7.80 min.). 79-А B-1. (3-Trifluoromethylphenyl)-amide (-)-5-I(I6--1-cyclopropylaminoethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid. MS (IER) t/lg 482.1 (M-1); "H NMR (400 MHz, Meob) 5 ppm 8.66 (5.1 N), 8.35 (a, 9-8.84 Hz, 1 N), 8.06 (5.1 N) , 7.94 (a, 9-3.54 Hz, 1 N), 7.89 (a, 9U-8.34 Hz, 1 N), 7.56 (I, U-7.96 Hz, 1 N ), 7.A1 (9, 9-2.27 Hz, 1 H), 7.44 (a, O0-7.83 Hz, 1 H), 7.11 (aa, 2U-9.09, 2, 27 Hz, 1 N), 7.02 (5, 1 N), 6.74 (a, y-3.79 Hz, 1 N), 3.89 (a, 9U-6.82 Hz, 1 N) . ). t/2 482.1 (M--1); "H NMR (400 MHz, Meob) 5 parts/million 8.66 (y, 9U-1.01 Hz, 1 H), 8.35 (a, 2-9.09 Hu, 1 H), 8.06 (5, 1 H), 7.94 (a, 9-3.54 Hz, 1 H), 7.90 (a, U-8.08 Hz , 1 H), 7.57 (i, y9-8.08 Hu, 1 H), 7.42 (a, 9-2.27 Hu, 1 H), 7.44 (a, O-7.83 Hz, 1 N), 7.11 (yes, U-8.84, 2.27 Hz, 1 N), 7.02 (5, 1

H), 6.74 (0.9-3.79 Hu, 1 H), 3.89 (ad, 9U-6.82 Hu, 1 H), 1.98 (aa, 9-10.48, 2 .91 Hu, 1 H), 1.35 (a, U-6.82 Hz, Z

H) 0.31 - 0.43 (t, 4 H).

Example 80 (3-Trifluoromethylphenyl)-amide of 5-(2-cyanopyridin-4-yloxy)-indole-1-carboxylic acid. about EU in

M (in) N

M

BIVAY-H (0.75 ml, 1.0 M) is added to a solution of tert-butyl ether 4-(1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyridin-2- of carboxylic acid (0.250 g, 0.502 mmol) in DCM (5 mL). After 1 h, the solution was allowed to warm to RT. After another 1 h, the reaction was quenched with a saturated aqueous solution of potassium sodium tartrate. Workup was carried out with DCM and a saturated aqueous solution sodium potassium tartrate After drying, the crude aldehyde is concentrated and used in the next step without treatment.

The aldehyde obtained above was taken up in DCM (2 mL) and EM (0.08 mL) and hydroxylamine hydrochloride (0.021 g, 0.300 mmol) were added. After 1.5 hours add EizM (0.9 mL), then methanesulfonyl chloride (0.025 mL, 0.300 mmol). After stirring overnight, the reaction mixture was diluted with DCM and washed with brine. The residue is purified using semi-preparative HPLC (10-90 95 ACN/H2O with the addition of 0.1 95 MNAOH) and the desired compound is obtained. MS (IER) t/2 423.1 (M--1).

Example 81 (3-Trifluoromethylphenyl)-amide of 5-(2-(1-hydroxy-1-methylethyl)-pyridin-4-yloxy|-indole-1-carboxylic acid. o ES vv;

M but o nn

Magnesium methyl iodide (0.30 ml, 3.0 M) is added to a solution of tert-butyl ether 4-(11-(3-

trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyridine-2-carboxylic acid (0.150 g, 0.302 mmol) in THF (5 mL). After stirring overnight, the reaction mixture was diluted with MeOH (5 mL) and worked up with DCM and pH 7 buffer. After concentration, the residue was purified by FFC (80-100 96 EAs/heptane) to give the desired compound. MS (IER) t/2 456.1 (M-H1).

Example 82 82-А. 5-(6-Chloropyrimidine-4-yloxy)-1H-indol

Mo M

N

SI

To a solution of 1H-indol-5-ol (3.0 g, 22.54 mmol) and 4,6-dichloropyrimidine (3.7 g, 24.8 mmol) in acetonitrile (40 mL) was added DBU (3.52 mL , 24.8 mmol). The mixture is stirred overnight. After removal of acetonitrile, the residue is partitioned between EOAc and water. Then the aqueous phase is further extracted with EAs. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Then, the residue is purified by KFC (0-30 96 EOAc/heptane) and the desired compound is obtained. MS (IER) t/2 246.1 (M.n1). 82-8. 82-8-1: tert-butyl ether of 4-I(6-(1H-indol-5-yloxy)-pyrimidin-4-yl|-3,6-dihydro-2H-pyridine-1-carboxylic acid and 82- 8-2: tert-butyl ether of 4-I(6-(1H-indol-5-yloxy)-pyrimidin-4-yl|-3,4-dihydro-2H-pyridine-1-carboxylic acid.

Yes, yes

M M r

Household items 82-8-1 82-8-2

A mixture of 4-(4,4,5,5-tetramethyl-|/1,3,2)dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ether (1, 24 g, 4.0 mmol), 5-(b-chloropyrimidin-4-yloxy)-1H-indole (750 mg, 3.05 mmol), tetrakistriphenylphosphine)palladium (106 mg, 0.03 mmol) and potassium carbonate ( 1.26 g, 9.15 mmol) in DMF (15 mL) in a sealed microwave reactor vessel was degassed and then purged with nitrogen. This mixture is then stirred at 150 °C in a microwave reactor for 40 min. After cooling the mixture to RT, it is diluted with EAs/heptane (8:2) and washed with water (3x) and brine, and the organic layer is dried over anhydrous Ma5O, filtered and concentrated. The residue was then purified by KFC (0-5095 EAs/heptane) and both desired compounds (B-1 and B-2) were obtained. MS (ER) t/2 393.1 (M--1). 82 - C. Tert-butyl ether of 4-I(6-(1H-indol-5-yloxy)-pyrimidin-4-yl|-piperidine-1-carboxylic acid

J

M

N

I and: 95 Ra/C (20 mg) is added to a solution of tert-butyl ether 4-(6-(1H-indol-5-yloxy)-pyrimidin-4-yl|-3,6-dihydro-2H-pyridine -1-carboxylic acid and tert-butyl ether of 4-I(6-(1H-indol-5-yloxy)-pyrimidin-4-yl|-3,4-dihydro-2H-pyridine-1-carboxylic acid (200 mg ) in EtOAc (5 mL). The mixture was stirred under hydrogen (1 atm) overnight and then filtered through celite and concentrated in vacuo to afford the title compound. MS (ER) t/2 395.0 (M-n1 ).

Example 83 83-А. 4-16-1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ether.

Ve Zh sha

M u (c) d -

H o i

n-butyllithium (1.6 M in hexane, 0.22 ml) was added to a solution of 2,2,6,6-tetramethylpiperidine (46.8 mg, 0.33 mmol) in 10 ml of THF at -78 "C, then tert-butyl ether 4-(6-(1H-indol-5-yloxy)-pyrimidin-4-yl|-

of 3,6b-dihydro-2H-pyridine-1-carboxylic acid (130 mg, 0.33 mmol), maintaining the temperature below -70 °C. The reaction mixture is stirred for 10 min., then 1-isocyanato-3-trifluoromethylbenzene ( 61.7 mg, 0.33 mmol). The reaction mixture was slowly warmed to room temperature and stirred at RT overnight. Concentrated under reduced pressure, then the residue was partitioned between EOAc and water. The aqueous layer was further extracted with EOAc. The combined organic layers are washed with saline solution, dried over anhydrous

Mag5O»x, filter and concentrate. Then the residue is purified using KFC (0-50 95

EOAc/heptane) and obtain the desired compound. MS(PER) t/2 579.9 (M'-1).

The following compounds are obtained by a similar method. 83-8. 4-16-11-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyrimidin-4-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ether.

EE ra

FOR

M o

M their ef;

H

(c) z

MS(IER) t/» 579.9 (M--1). 83-S. 4-16-1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyrimidin-4-yl-piperidine-1-carboxylic acid tert-butyl ether.

R E r

BOOTS

M

M (c)

Sh-

SO about

HM about and

MS(IER) t/» 581.9 (M--1).

Example 84 84-А. (3-Trifluoromethylphenyl)-amide 5-(6-(1,2,3,6-tetrahydropyridin-4-yl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid

E.S

Ge) With in;

M. 22 u

M y o nn

M

N

TFC (0.5 ml) is added to a solution of tert-butyl ether 4-16-(1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyrimidin-4-yl)-3,6-dihydro-2H -pyridine-1-carboxylic acid (160 mg, 0.276 mmol) in

DCM (5 ml). The solution is stirred overnight and then the solvent is removed. The residue is dissolved in

DCM and washed with a saturated aqueous solution of MansSoOz. The product is further extracted with EOAc (2 x 25 ml) and the combined organic layers are washed with brine, dried over anhydrous Mag5O", filtered and concentrated. Then the residue is purified using KFC (0-10 95 2 M MHz in Meon/dxHmM) and the desired compound is obtained. MS (ER) t/2 480.1 (M--1); "H NMR (400 MHz, mMeor) b frequency/million 8.60 (5.1 N), 8.36 (y, 9U-8.84 Hz, 1 N), 8.06 (5.1 N) , 7.95 (a, 9U-3.79 Hz, 1 N), 7.91 (c, 1

H), 7.58 (Y, 9-8.21 Hz, 1 H), 7.45 (5, 1 H), 7.42 (a, 9-2.27 Gu, 1 H), 7.12 (aa, O-8.97, 2.40 Hz, 1 H), 7.00 (a, 9-3.35, 1.74 Hz, 1 H), 6.98 (5, 1 H), 6 .75 (a, U-3.79 Hz, 1 N), 3.70 - 3.75 (t, 2 N), 3.07 (I, 9-5.81 Hz, 2 N), 1.87 (ada, U-6.44, 3.41, 3.28 Hz, 2 N).

The following compounds are obtained by a similar method. 84-8. 5-(6-(1,2,3,4-tetrahydropyridin-4-yl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide.

EE

IS

N

M and o

M kwa ze;

X o) zm

MS (IER) t/2 480.1 (M-e1); "H NMR (400 MHz, Meor) 5 parts/million 8.59 (y, 9U-1.01 Hz, 1 H), 8.63 (a, 9-1.01 Hz, 1 H), 8, 35 (a, 9U-8.34 Hz, 1 H), 8.06 (5, 1 H), 7.94 (a, 9-2.78 Gu, 1 H), 7.54 - 7.60 ( t, 2 H), 7.41 (a, 9-1.77 Hz, 2 H), 7.44 (a, U-7.83 Hz, 1 H), 7.11 (aa, 9U-9, 09, 1.52 Hz, 1 N), 6.84 (5, 1 N), 6.74 (a, U-3.79

Hu, 1 H), 4.33 - 4.35 (t, 1 H), 3.03 - 3.21 (t, 2 H), 2.76 (ai, 9-11,37,215 Hz, 2 H) . 84-60. (3-Trifluoromethylphenyl)-amide of 5-(b-piperidin-4-ylpyrimidin-4-yloxy)-indole-1-carboxylic acid.

IF) o Z fi;

M. 2 U

M o nn

M

N

MS (ER) t/2 482.1 (M--1); "H NMR (400 MHz, Meob) b frequency/million 8.60 (5.1 H), 8.35 (a, U-8.84 Hz, 1

H), 8.06 (5, 1 H), 7.94 (a, 9-3.79 Hz, 1 H), 7.89 (a, 9-8.08 Hz, 1 H), 7.57 (I, 9-8.08 Hz, 1 N), 7.40 (a, 9-2.27

Hz, 1 H), 7.44 (a, 20-7.83 Hz, 1 H), 7.10 (aa, U-8.97, 2.40 Hz, 1 H), 6.85 (5, 1 H), 6.74 (y, 92-3.79 Hz, 1 H), 3.13 (9, 9-12.63 Hz, 2 H), 2.70 (Id, 9-12.44, 2.40 Hz, 2 N), 2.66 - 2.83 (t, 1 N), 1.89 (0.9-1213 Hz, 2 N), 1.69 (ad, 9U-12.63, 3.79 Hz, 2 N).

Example 85 (3-Trifluoromethylphenyl)-amide (z)-5-16-Hydroxy-(1-methyl-1H-imidazol-2-yl)-methyl|-pyrimidin-4-yloxy)-indole-1-carboxylic acid. o) o) Z zva;

MO M x h-k and ON o nn

M

n-butyllithium (1.6 M in hexane, 0.44 ml) was added to a solution of 1-methyl-1H-imidazole (77 mg, 0.94 mmol) in 5 ml of THF at -78 "C. The solution was stirred at -78 "With for 1 hour. then a solution of 5-(6-formylpyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide (200 mg, 0.47 mmol) in THF (5 mL) was added. The reaction mixture was allowed to warm to RT and stirred overnight. The reaction is then quenched with water and then extracted with EtOAc (3x25 mL). The combined organic layers are washed with brine, dried over anhydrous Mag50, filtered and concentrated.

Then the residue is purified using semi-preparative HPLC (C18; 30-100 95 ACN/HgO with the addition of 0.1 95 TFA) and the desired compound is obtained. The fractions are combined and the pH value is adjusted to 9 with sodium bicarbonate. The product is extracted with EOAc. The organic layer is washed with saline, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated and the desired compound is obtained. MS (IER) t/2 509.0 (M--1); "H NMR (400 MHz, MeOb) 5 ppm 8.59 (y, 9-1.01 Hu, 1 H), 8.36 (a, 9U-9.09 Hu, 1 H), 8, 06 (5, 1 N), 7.94 (a, 9-3.79 Hz, 1 N), 7.90 (a, 9-7.83 Gu, 1 N), 7.57 (t, 2 N ), 7.46 (0.9-2.02 Hu, 1 H), 7.29 (5.1 H), 7.16 (aa, 9-8.97, 2.40 Hz, 1 H), 7.05 (a, 9-1.26 Gu, 1

H), 6.85 (a, 9-1.26 Gu, 1 H), 6.75 (j, U-3.54 Hz, 1 H), 5.91 (5, 1 H), 3.72 (5, Z H).

Example 86 86-А. M-(4-Fluoro-3-(trifluoromethyl)phenyl)-5-(6-(methylsulfonylmethyl)-pyrimidin-4-yloxy)-1H-indole-1-carboxamide.

E.S

Ge) Z

SO and

M. and M o Kh-m

In o nn (c)

To a solution of (6-(1-(4-fluoro-3-"(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)pyrimidin-4-yl)umethylmethanesulfonate (0.22 g, 0.42 mmol) in 5 ml of THF and 3 ml of DMF add May (0.095 g, 0.63 mmol), followed by DIPEA (0.11 ml, 0.63 mmol) and sodium methanesulfinate (0.129 g, 1.26 mmol). The mixture is stirred at CT for 2 hours. and then diluted with EAs, washed with a saturated solution of Mansoz (x2), saline solution, and the organic layer was dried over Ma»5O»x. After concentration, the residue is purified by HPLC (20-90 95 EIHOAc/heptane) and then by semi-preparative HPLC (22-65 956 ACN/HgO with the addition of 0.195 MNAOH) and the desired compound is obtained. MS (ER) t/2 509.0 (M--1); "H NMR (400 MHz, DMSO-av) 6 ppm 10.38 (Bg. 5., 1 H), 8.78 (y, 9-1.0 Hz, 1 H), 8.30 ( a, 2-8.8 Hz, 1 H), 8.06 - 8.17 (t, 2 H), 7.97 - 8.05 (t, 1 H), 7.58 (I, U-9 ,7 Hz, 1 H), 7.52 - 7.54 (t, 1 H), 7.21 (a, 9U-1.0 Hz, 1 H), 7.18 (aa, 9U-9.0 , 2.4 Hu, 1 H), 6.82 (aa, 9-3.7, 0.6 Hz, 1 H), 4.70 (5.2 H), 3.11 (5, C H) .

The following compounds are obtained by a similar method. 86-88. 4-fluoro-5-(6b-methanesulfonyl-methylpyrimidin-4-yloxy)-indole-1-carboxylic acid (5-tert-butylisoxazol-3-yl)y-amide

WHAT else c) 55 i-

M ah

X che c) we

IS

MS (ER) t/ 488.1 (M-1); "H NMR (400 MHz, Meob) b frequency/million 8.78 (y, 9-1.01 Hz, 1 H), 8.21 (a, y-4.04 Gu, 1 H), 8, 13 (a, 9-9.09 Hu, 1 H), 7.38 (a, 9-1.01 Hu, 1 H), 7.34 (5, 1 H), 6.91 (a, 9- 3.79 Hu, 1 H), 6.68 (5, 1 H), 4.74 (5, 2 H), 3.14 (in, 3 H), 1.935 (5, 9 H).

Example 87 87-А. 16-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-yl|-methanol

IS

(c) ») o

MO M

N on

5-(6-benzyloxymethylpyrimidin-4-yloxy)-4-fluoro-2-methyl-1H-indole (2.59 g, 7.13 mmolOl) in methanesulfonic acid (15 ml) and the solution is heated in a microwave reactor at 100 "C for 5 minutes. Then the reaction mixture is diluted with 250 ml of EOAc and a saturated aqueous solution of MnSOOz. The aqueous layer is washed with EtOAc (4x100 ml). The organic phases are combined, washed with with (2 x 150 ml) water, then (1 x 60 ml) brine, dried over Mag50O5 and concentrated in vacuo. The residue was purified by FCX (0-20 956 Meon/DXM) to obtain the desired compound. MS (ER) t/2 274 ,1 (M.n1). 87-8. 4-Fluoro-5-(6-methanesulfonylmethylpyrimidin-4-yloxy)-2-methyl-1H-indole.

IS

E. Zh M o v, (6)

16-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-yl|-methanol (1 g, 3.66 mmol) was placed in DCM (40 mL). Add methanesulfonyl chloride (0.34 mL, 4.39 mmol) and DIPEA (0.89 mL, 5.12 mmol) and then after 15 min. the reaction mixture is diluted with water and extracted with DCM.

The organic phase is washed with saline, dried over Mag25O4 and concentrated in a vacuum.

The obtained methanesulfonic acid 6-(4-fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-ylmethyl ether is dissolved in DMF (10 ml) and sodium methanesulfinate (1.12 g, 11.0 mmol) and the reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is subjected to distribution between

HgO and ethyl acetate. The organic phase is washed with saline, dried over Mag5O4 and concentrated in a vacuum. The residue is purified by KFC (0-10 906 MeOOn/DHM) and the desired compound is obtained. MS (IER) t/2 336.0 (M--1) 87-06. (3-Trifluoromethylphenyl)-amide of 4-fluoro-5-(6b-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methylindole-1-carboxylic acid.

IS

E.S o) Z

С СО»

M. 2 M o X-m r o H (6) 4-Fluoro-5-(b-methanesulfonylmethylpyrimidin-4-yloxy)-2-methyl-1H-indole (250 mg, 0.745 mmol) in

THF (10 ml) is cooled to -78 "C and a 1 M solution of GINMO5 in THF (1.86 ml, 1.86 mmol) is added.

After 12 minutes. 1-isocyanato-3-(trifluoromethyl)-benzene (0.12 ml, 0.895 mmol) is added and the reaction mixture is stirred at -78 "C. After 1 hour, the reaction is stopped with a saturated aqueous solution of MNACI and then extracted with (3x100 ml) EAs. The organic phases are combined and washed with brine, dried over Mag50"x and concentrated in vacuo. The residue is purified with (0-3 Pho meon/ldhm) to give (3-trifluoromethylphenyl)-amide 4-fluoro-5 -(6-methanesulfonylmethylpyrimidin-4-yloxy)-2-methylindole-1-carboxylic acid. 99 (5, 1 N), 8.77 (a, 9-1.01 Hz, 1 N), 8.12 (5, 1 N), 7.91 (5, 1 N), 7.66 (5 , 1 H), 7.53 (0, U-9.35 Hz, 2 H), 7.36 (a, 9-1.01 Gu, 1 H), 7.20 (a, 2-7.33 Hz, 1 N), 6.64 (5, 1

Н), 4.73 (5.2 Н), 3.13 (5, З Н), 2.59 (5, З Н).

The following compounds are obtained by a similar method. 87-0.. (2-Fluoro-3-trifluoromethylphenyl)-amide of 5-(b-methanesulfonylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid.

M o EzS

Su

MO M o X-m v o nn (v)

MS (IER) t/2 509.0 (M--1); "H NMR (400 MHz, DMSO-dv) 6 parts/million 8.78 (y, 9U-1.01 Hz, 1 H), 8.27 (a, 928.84 Gu, 1 H), 8, 11 (a, 9-3.54 Gu, 1 H), 7.94 (5, 1 H), 7.71 (5.1 H), 7.47 - 7.54 (t, 2 H), 7 ,16 - 7,21 (t,2

H), 6.83 (8, 9U-3.79 Hz, 1 H), 4.69 (5, 2 H), 3.11 (5, C H). 87-E. 4-Fluoro-(3-trifluoromethylphenyl)-amide of 5-(6b-methanesulfonylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid.

Y IF) fe, Z

With SO

MO M o Kh-m

In o nn (c)

MS (ER) t/2 509.0 (M--1); "H NMR (400 MHz, DMSO-dv) b freq./million 10.50 (bBg. 5., 1 N), 8.79 (5.1 N), 8.09 - 8.24 (t, Z H), 7.97 (a, 9-8.08 Hz, 1 H), 7.66 (I, 9U-7.96 Hz, 1 H), 7.51 (a, 9-7.83 Hz, 1 H), 7.38 (5, 1

H), 7.33 (I, 9U-8.34 Hz, 1 H), 6.94 (a, 9U-3.79 Hz, 1 H), 4.74 (5.2 H), 3.14 (5, Z H).

Example 88 (5-Methylpyridin-3-yl)-amide of 5-(b-hydroxymethylpyrimidin-4-yloxy)-indole-1-carboxylic acid.

M (c); -sh i If; same

M. 2 M M

M

Mon o N

Urea is obtained similarly to the preparation in example 51-A by combining the compound of example 14-A with 3-amino-5-methylpyridine followed by removal of the benzyl protecting group, as described in example 16-A. MS (ER) t/2 376.0 (M-n1).

Example 89 1-((6-(1-(4-Fluoro-3-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-pyrimidin-4-yl)umethyl)piperidine-4-carboxylic acid. (6) 02505 5

MO 2 M

hmm se

M o nn (6) on

To a solution of methyl 1-((6-(1-(4-fluoro-3-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)pyrimidin-4-ylmethyl)piperidine-4-carboxylate (0.13 g , 0.228 mmol) in 40 mL of THF/HgO (3:1) is added with a 2 M aqueous solution of ION (0.23 mL). The mixture is stirred at RT for 3.5 h and then concentrated and purified by semi-preparative HPLC (12- 48 95 ACN/NgO with the addition of 0.1 95 TFC) and obtain the desired compound. MS (ER) t/2 558.1 (M--1); "H NMR (400 MHz, DMSO-α) b ch./ million 10.43 (5, 1 N), 9.93 -10.12 (t, 1 N), 8.88 (5, 1 N), 8.32 (a, 9-91 Hz, 1 N), 8.08-8.17 (t, 2 H), 7.96 - 8.06 (t, 1

H), 7.58 (I, U-9.9 Hz, 1 H), 7.52 (а, 9-2.5 Hz, 1 H), 7.25 (Brg. 5., 1 H), 7.17 (aa, U-9.0, 2.4 Hz, 1 H), 6.83 (a, 9-3.5 Hz, 1 H), 4.39 -4.60 (t, 2 H ), 3.45 - 3.57 (t, 2 H), 2.98 - 3.17 (t, 2 H), 1.95 - 2.14 (t, Z H), 1.73 - 1, 91 (t, 2 N).

Example 90 90-А. (73-5-(6-"(Benzyloxymethyl)pyrimidin-4-yloxy)-M-(4-methoxy-3-"trifluoromethyl)phenyl)-1H-indole-1-carboxamide. o) -

There is IF; at)

M. U. S

M

(c) about nn

KDI (1.17 g, 7.24 mmol) is added to a solution of 5-(6-(benzyloxymethyl)pyrimidin-4-yloxy)-1H-indole (0.8 g, 2.41 mmol) in 35 ml of DHE. followed by TEA (1 mL, 7.24 mmol). The mixture was stirred at RT overnight and then 4-methoxy-3-(trifluoromethyl)aniline (1.38 g, 7.24 mmol) was added, followed by stirring for 4 days. The reaction mixture is diluted with DCM, washed with a saturated aqueous solution of MaHsSoOz (x2), saline solution, and the organic layer is dried over Ma»b5O»4. After concentration, the residue is purified using KFC (5-60 96 EAs/heptane) and the desired compound is obtained. MS (IER) t/2 549.1 (M.n1).

90-8. 5-(6-(2-Hydroxyethylamino)methyl)pyrimidin-4-yloxy)-M-(4-methoxy-3-trifluoromethyl)phenyl)-1H-indole-1-carboxamide. poshi on m on

NN on

It is obtained by a method similar to that described in example 19. MS (IER) t/2 502.1 (M-41); "H NMR (400 MHz, DMSO-av) 6 ppm 10.15 (Bg. 5., 1 H), 8.65 (a, 9U-1.0 Hz, 1 H), 8.28 ( a, 2-91 Hz, 1 H), 8.10 (a, y-3.8 Hz, 1 H), 7.95 (a, 9U-2.8 Hz, 1 H), 7.91 (aa , U-8.8, 2.5 Hz, 1 H), 7.48 (а, 9-23 Hz, 1 H), 7.33 (y, 9-91

Hz, 1 H), 7.13 (aa, U-8.8, 2.3 Hz, 1 H), 7.09 (5, 1 H), 6.79 (a, 9U-3.8 Hz, 1 H), 3.90 (5, Z H), 3.78 (5, 2 H), 3.45 (I, 9U-5.7 Hz, 2 H), 2.59 (I, U-5 .8 Hz, 2 N).

Example 91 91-А. (3Z-Trifluoromethylphenyl)-amide 5-(6-(cyanotrimethylmilanyloxymethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid.

BE

IS

Ex

M their o;

M chu (c) more

To a solution of 5-(6-formylpyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide (200 mg, 0.471 mmol) and methyltriphenylphosphonium iodide (19 mg, 0.05 mmol) in DCM ( 5 ml) TMZSM (0.063 ml, 0.471 mmol) is added with a syringe. The mixture is stirred for 3 hours, then it is diluted with DCM (20 ml), washed with water, brine, and the organic layer is dried over NaClO, filtered and the solvent is removed to obtain the desired compound, which is used in the next step without further purification. MS (ER) t/l 525.9 (M.-1). 91-8. (3-Trifluoromethylphenyl)-amide /(g)-5-16-(2-amino-1-hydroxyethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid. (in)

Su

What about

MN, M but on

Raney nickel (20 mg) is washed with Meon (3x5 ml), then a solution of (5)-(3-trifluoromethylphenyl)-amide 5-16-(cyanotrimethyl-milanyloxymethyl)-pyrimidin-4-yloxy|-indol-1- carboxylic acid (100 mg, 0.19 mmol) in MeonH (5 mL) and THF (3 mL). The mixture is stirred in an atmosphere of NO (from a cylinder) during the night. The mixture is filtered through celite and the filtrate is concentrated.

Then the residue is purified by KFC (0-10 90 MeOnH/E(OAc)) and the desired compound is obtained. MS (IR) t/2 458.1 (M--1); "H NMR (400 MHz, DMSO-dv) 5 parts/million 8.60 - 8.70 (t, 1 H), 8.36 (a, 9-8.59 Hz, 1

H), 8.06 (Bg. 5., 1 H), 7.90 (a, 9-7.58 Hz, 1 H), 7.95 (a, 9U-3.28 Hz, 2 H), 7.73 (a, 9-4.55 Hz, 1 H), 7.57 (Her, y-7.83 Hz, 1 H), 7.37 - 7.47 (t, C H), 7, 12 (a, 9U-8.59 Hz, 2 H), 7.04 (5, 1 H), 6.75 (Bg. 5., 1 H), 4.89 (a, 9-5.05 Hz , 1 N), 3.67 (aa, 9U-12.25, 7.71 Hz, 2 N).

Example 92 92-А. (3-Trifluoromethylphenyl)-amide 5-I(6-(5)-2-carbamoylpyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid

E.S

Ge) Z tva;

M. U

M

M o nn c)

MH,

To a solution of 5-(6-formylpyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide (60 mg, 0.141 mmol) in Meon (5 mL) was added ASON (0.1 mL), then amide (5)-pyrrolidine-2-carboxylic acid (19 mg, 0.169 mmol). The mixture is stirred for 10 min., then add mvnz (cM). The resulting mixture is stirred overnight. Then the reaction is stopped with a saturated aqueous solution of sodium bicarbonate. The product is extracted with EOAc (3). The combined organic layers were washed with water and brine and then dried over magnesium sulfate, filtered and the solvent removed. Then the residue is purified by means of KFC (0-10 956, 2M solution of ammonium in MeOn/DHM) and the desired compound is obtained. MS (ER) t/2 524.9 (M--1); "H NMR (400 MHz, MeOb) b frequency/million 8.63 (5.1

H), 8.34 (a, U-9.09 Hz, 1 H), 8.06 (5, 1 H), 7.94 (a, 9-3.79 Hu, 1 H), 7.89 (a, 9-7.83 Gu, 1 H), 7.57 (I, U-8.08

Hz, 1 N), 7.41 (a, 9-2.53 Hz, 1 N), 7.44 (a, 9-8.59 Hz, 1 N), 7.07 - 7.14 (t, 1 H), 7.12 (a, 0-227 Hz, 1 H), 6.74 (y, 9-3.54 Gu, 1 H), 3.94 (a, 9-14.65 Hz, 1 H), 3.66 (y, 9-14.65 Hz, 1 H), 3.23 (aa, 9-9.73, 5.18 Hz, 1

H), 3.12 (ad, 9-8.72, 4.67 Hu, 1 H), 2.46 (I, 2-8.21 Hu, 1 H), 2.23 (1, U-9 .09, 4.29 Hz, 1 N), 1.79 - 1.91 (t, Z

N).

The following compounds are obtained by a similar method. 92-88. (3Z-Trifluoromethylphenyl)-amide 5-(6-(1-2-carbamoylpyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid.

E.S o) With c;

M. U

M

Shu; oh nn what

MH,

MS (ER) t/2 524.9 (M--1); "H NMR (400 MHz, Meor) b frequency/million 8.63 (5.1 H), 8.34 (a, 9U-9.09 Hz, 1

H), 8.05 (5, 1 H), 7.93 (a, 9-3.79 Hz, 1 H), 7.89 (a, 9-8.08 Hz, 1 H), 7.56 (I, 9U-7.96 Gu, 1 H), 7.40 (a, 9-2.27

Hz, 1 N), 7.43 (a, 9-7.83 Hz, 1 N), 7.06 - 7.13 (t, 1 N), 7.11 (a, 9U-2.53 Hz, 1 H), 6.73 (y, 9-3.54 Hz, 1 H), 3.93 (a, 9-14.65 Hz, 1 H), 3.65 (a, 9U-14.65 Hz , 1 H), 3.22 (da, 9-9.73, 5.18 Hz, 1 H), 3.10 (a, 9-4.55 Gu, 1

H), 2.44 (I, 20-8.08 Hz, 1 H), 2.21 (ad, O-7.83, 2.78 Hz, 1 H), 2.15 - 2.36 (t , 1 H), 1.78 - 1.92 (t, C H). 92-6b. (3-Trifluoromethylphenyl)-amide 5-N6-(5)-2-ethylcarbamoylpyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid.

E.S

Ge) With in;

M u

M

M o nn c)

J

MS (ER) t/2 552.9 (M--1); "H NMR (400 MHz, Meor) b frequency/million 8.66 (5.1 H), 8.36 (a, U-8.84 Hz, 1

H), 8.06 (5, 1 H), 7.95 (a, 9-3.79 Hz, 1 H), 7.90 (a, 9-6.57 Hz, 1 H), 7.57 (, 9-7.96 Hu, 1 H), 7.42 (a, 9-2.27

Hz, 2 N), 7.11 (yes, U-8.97, 2.40 Hz, 1 N), 7.07 (5, 1 N), 6.75 (y, 9-3.79 Hz, 1 H), 3.88 (a, U-14.40 Hz, 1 H), 3.69 (a, 9-14.40 Gu, 1 H), 3.18 (da, U-7.28, 1.14 Hz, 2 N), 3.09 - 3.27 (t, 2 N), 2.44 - 2.52 (t, 1 N), 2.21 (19, 9-9.09, 4 .04 Hu, 1 H), 1.74 - 1.687 (t, C H), 1.07 (I, U-7.33 Hz, C H).

Example 93 93-А. Tert-butyl ether of (z)-3-(16-P1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyrimidin-4-ylmethyl)-amino)-pyrrolidin-1-carboxylic acid.

E (F)

Oh Mo

In Olya (in) MN "that ef)

H o i

To a solution of methanesulfonic acid (g)-6-(11-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyrimidin-4-ylmethyl ether (80 mg, 0.158 mmol) in THF (5 ml) was added tert- 3-aminopyrrolidine-1-carboxylic acid butyl ether (88 mg, 0.474 mmol) and diisopropylethylamine (61 mg, 0.474 mmol).

The resulting solution was stirred at 60 °C overnight. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with water and then with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed. The residue was purified by KFC (0 -10 96 MeOn/DHM) and obtain the desired compound. MS (IER) t/2 597.2 (M-n1).

The following compounds are obtained by a similar method. with. and MS (ER)

ST osvuannnianyam 000 snyameyum Wed

Vo (MeOb) 5 parts/million 8.59 (5.1

E H), 8.39 (rg. 5., 1 H), 8.14 (4, oh 3-8.84 Hz, 1 H), 7.72 (5.1 H), o - 7.67 (a, U-8.08 Hz, 1 N), 7.52 (a,

M-th o uU-3.79 Hz, 1 H), 7.28 - 7.39 (t, 1 H), 7.23 (Bi. 5., 1 H), 6.95-

Z3-V Fi ie 7.01 (t, 2 H), 6.47 (4, 9-2.78 582.2 ohm Hu, 1 H), 3.63 (a, 9U-8.34 Hz, 2 tert-butyl ether (g)-1-(6-I1-(3-I), 2.79 2.91 (t, C H), 2.65 (0, trifluoromethylphenylcarbamoyl)-1 H-indole-5- | 976 .06 Hz, 1 NU, 2.53 (d, 9-7.75 yloxy|-pyrimidin-4-ylmethyl)-pyrrolidin-3- Hz, 1 NU, 1.99 (5 9-6.95 Hz, 2 of carboxylic acid NU, 1.35 (5.9 N).

Re

E (meob) 6 parts/million 8.63 (5, 1 (o) H), 8.34 (a, 9U-9.09 Hz, 1 H), uche 8.06 (5, 1 H), 7.94 (a, 9U-3.79 Hz, o Go 1 H), 7.89 (a, U-7.83 Hz, 1 H), -x x 7.57 (I, U-8.08 Hz, 1 N), 7.44 (y, 93-C N uU-8.59 Hz, 1 N), 7.07 - 7.14 (t, 5BBZ 2

M M Z H), 6.74 (a, 9U-3.54 Hz, 1 H), "

S h. p 4.85 (5, 2H) 3.94 (t, 1 H), 3.66 o M (t, 1 H), 3.23 (t, 1 H), 3.12 (t, (Z- trifluoromethylphenyl)-amide (5)-5-16-I(3-1 H), 2.45 (t, 1 H), 2.23 (t, 1 (acetylmethylamino)-pyrrolidin-1-ylmethyl|- /H ), 2.02 (5, ZH), 1.79 - 1.91 (t, pyrimidine-4-yloxy)-indole-1-carboxylic acid 4 H)

E is (meOb) b freq./million 8.64 (a,

E 3-1.01 Gu, 1 H), 8.35 (a, 9U-9.09

Hz, 1 N), 8.06 (5, 1 N), 7.95 (y,

MH -3.79 Hz, 1 H), 7.90 (a, 9U-7.83 o g I Hz, 1 H), 7.57 (i, U-7.96 Hz, 1

Sh- o H), 7.42 (y, 9-2.02 Hz, 1 H), 93-00 H 7.44 (a, 9-7.83 Hz, 1 H), 7.12 524.9 and m (ad, 9U-8.97, 2.40 Hz, 1 N), 7.07

C -- p (a, 9U-1.01 Hz, 1 H), 6.75 (y, mice 9-3.79 Hz, 1 H), 3.77 (9, 9U-4.55 (Z- trifluoromethylphenyl)-amide (z)-5-(6-(3- Hz, 2 H), 2.98 (t, 1 H), 2.89 (t, carbamoylpyrrolidin-1-ylmethyl)-pyrimidin-4- | 4 H), 2.68 - 2.79 (t, C H), 2.04 yloxy|-indole-1-carboxylic acid t, 2 MH).

E and (MeOb) b freq./million 8.63 (a, and (9) 91.01 Hz, 1 N), 8.35 (a, 9-9.09 and» r HC, 1 N), 8 .06 (5.1 N), 7.94 (y,

M 93.79 Hz, 1 H), 7.90 (a, 9-8.08 (9) MH | Hz, 1 H), 7.57 (Her, 9-7.96 Hz, 1 - H), 7.42 (0, 9-2.53 Hz, 1 H), 93-E M ek 7.44 (a, 9-7.83 Hz, 1 H), 7.11 512.9 fi | (aa, 9U-8.97, 2.40 Hz, 1 N), 7.04

Choy (a, 9-1.01 Hz, 1 H), 6.74 (a, (3-trifluoromethylphenyl)-amide 5-(6-Z By 5 oc) Ky in, lich

I(dimethylcarbamoylmethylamino)-methyl-Hz 6 n) 7 I I pyrimidine-4-yloxy)-indole-1-carboxylic acid (meob) b parts/million 8.60 (a,

EE 91.01 Hz, 1 N), 8.35 (a, 9-9.09

E (in) HC, 1 N), 8.06 (5, 1 N), 7.88 - xx DL 7.95 (t, 1 N), 7.94 (4, 4-3.54 od Hz, 1 H), 7.57 (i, U-8.08 Hz, 1

What H), 7.42 (a, 9-2.53 HZ, 1 H),

M o 7.44 (a, 9-7.83 Hz, 1 H), 7.11 (her, 93-E - b 9-4.42 Hz, 1 H), 7.12 (a, 9-8 .84 5Z39 8 phi tm Hz, 1 N), 6.74 (y, 9-3.79 Hz, 1 '

H), 3.96 (5, 1 H), 3.74 (a, x o i y-15.16 Hz, 1 H), 3.63 (5, C H), methyl ether (5)-1 -(6-11-(3- 3.44 (aa, U-8.84, 5.56 Hz, 1 H), trifluoromethylphenylcarbamoyl)-1H-indole-5- | 3.08 (ada, U-8, 97, 6.69, 4.29 Hz, yloxy|-pyrimidin-4-ylmethyl)-pyrrolidin-2-1 NU, 2.54 (a, U-8.84 Hz, 1 H), carboxylic acid 2.15 (da , 9U-11.37, 2.78 Hz, 1 H), 1.81 - 1.96 (t, C H).

E E (meob) b frequency/million 8.60 (a, 9-1.01 Hz, 1 H), 8.35 (a, 9-8.84

R / HC, 1 H), 8.05 (5, 1 H), 7.93 (y, ho-y, 9-3.79 Hz, 1 H), 7.89 (y, U-8.08

HC, 1 H), 7.56 (i, U-8.08 Hz, 1 (c) M on NU, 7.41 (a, 9-2.27 HC, 1 H),

I- 7.43 (a, 9-7.83 Hz, 1 N), 7.13 (5, 93-06 M d 1 N)U, 7.11 (da, 9-8.97, 2.40 Gu, 555.9 her 1 N), 6.73 (y, 9U-3.79 Hz, 1 N),

X x p 4.35 (44, 9U-8.97, 2.65 Hz, 1 N),

Ohm 4.02 (y, 9-15.66 Hz, 1 H), 3.83 methyl ether (25, 4K)-4-hydroxy-1-16-(11- (5, 1 H), 3.73 (i, 9-7.83 Hz, 1 H), (3-trifluoromethylphenyl-carbamoyl)-1 H-indole | 3 64 (5, 3 H), 3.34 (i, 9-4.80 Hz, 5 -yloxy) -pyrimidin-4-ylmethyl)-pyrrolidin-2- 14 H), 2.53 (da, 9-10.11, 3.54 Hz, carboxylic acid 1), 2.04-2.18 (t , 2 H).

E is (MeО0b) 5 parts/million 8.66 (5.1

E o H), 8.36 (a, U-8.84 Hz, 1 H), dd-k // 8.06 (5, 1 H), 7.95 (a, 9-3.79 Hz,

M, 1 H), 7.90 (a, 9U-6.57 Hz, 1 H),

N | 7.57 (I, 9-7.96 Hz, 1 H), 7.42 (y, (c) M y-2.27 Hz, 2 H), 7.11 (aa, - 98.97, 2 ,40 Hz, 1 N), 7.07 (5.1 93-N М N), 6.75 (a, 9U-3.79 Hz, 1 N), 552.9

YM 3.88 (a, 9U-14.40 Hz, 1 H), 3.69

S k u (a, 9-14 40 Hz, 1 H), 3.18 (da, (c) M 97.28, 1.14 Hz, 2 H), 3.09 - (3-trifluoromethylphenyl)-amide 5-(6-((5)-2- 3.27 (t, 2 H), 2.44-2.52 (t, 1 ethylcarbamoylpyrrolidin-1-ylmethyl)- NI, 2.21 (19, Y- 9.09. 33 Hz, Z H)

Example 94 94-А. (3-Trifluoromethylphenyl)-amide (g)-5-I(I6-(pyrrolidin-3-ylaminomethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid. that) kA) and c;

M. 2 U

M

MN on Fr

N

Tert-butyl ether (53)-3-(16-1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyrimidin-4-ylmethyl)-amino)-pyrrolidin-1-carboxylic acid (20 mg, 3.30 mmol) was stirred in solution in DCM (2 mL) and TFA (0.5 mL) overnight. After removing the solvents, the residue is neutralized with a saturated aqueous solution of sodium bicarbonate. Then the mixture is extracted with EtOAc (3x) and the combined organic layers are washed with water, brine, dried over Mag5O54, filtered and the solvent is removed. The residue is purified using KFC (0-1095 2 M MHz in Meon/dcm) and the desired compound is obtained. MS (IER) t/2 496.8 (M--1); "H NMR (400 MHz, meob) b frequency/million 8.65 (5, 1 N), 8.36 (y, y-8.84 Hz, 1 N), 8.06 (5, 1 N) , 7.95 (y, 9-3.54 Hz, 1 N), 7.88 (5, 1 N), 7.57 (1, U-7.83 Hz, 1 N), 7.44 (a , 2-7,83

Hu, 1 H), 7.42 (a, 9-2.27 Hz, 1 H), 7.03 - 7.13 (t, 2 H), 6.75 (a, 9-3.79 Hz, 1 H), 3.80 - 3.85 (t, 2 H), 2.81 - 3.02 (t, Z H), 2.52-2.75 (t, 2 H), 2.19- 2.35 (t, 2 N).

The following compounds are obtained by a similar method. 94-8. (3-Trifluoromethylphenyl)-amide 5-(6-К15, 45)-1-(2,5-diazabicyclo(|2.2.1|hept-2-yl)umethyl|-pyrimidin-4-yloxy)-indol-1 -carboxylic acid. fe) oh,

Ma and M

N N

! Kh-ra (c

N SE,

MS (ER) t/2 509.1 (M-1); "H NMR (400 MHz, Meob) b frequency/million 8.61 (a, 9U-1.01 Hz, 1 H), 8.35 (y, y3-8.84 Hz, 1 H), 8, 06 (5, 1 H), 7.94 (a, 9-3.54 Hz, 1 H), 7.89 (a, U-8.59 Hz, 1 H), 7.56 (I, 9- 7.96 Hz, 1 H), 7.A1 (a, 90-2.27 Hz, 1 H), 7.40 - 7.45 (t, 1 H), 7.10 (da, 9-8, 97, 2.40 Hz, 1 N), 7.06 (5, 1 N), 6.73 (a, U-3.79

Hu, 1 H), 3.81 (a, 2-13.39 Hz, 1 H), 3.75 - 3.87 (t, 1 H), 3.57 (5, 1 H), 3.43 (5, 1 N), 3.09 (a, 9U-10.61 Hz, 1

H), 2.87 (yes, 9-9.85, 2.53 Hz, 1 H), 2.77 (yes, 9-10.48, 2.40 Gu, 1 H), 2.57 (a , 2U-9.85 Hz, 1 N), 1.85 (a, 95-10.36 Hz, 1 N), 1.58 (a, U-9.60 Hz, 1 N).

Example 95 (3-Trifluoromethylphenyl)-amide (g)-5-16-(3-carbamoylpyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid.

IF)

A) and seam;

M. U

M schi o nn o Mn,

3-Carbamoylpyrrolidine-1-carboxylic acid tert-butyl ether (0.22 g, 1.03 mmol) is dissolved in

DCM (5 ml). TFA (2 mL, 26.0 mmol) was added and the reaction mixture was stirred at RT overnight.

The solvent was removed in vacuo and THF (5.0 mL) was added, followed by methanesulfonic acid 6-(/1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyrimidin-4-ylmethyl ether (0.347 g, 0.685 mmol ) and

DIPEA (0.60 ml, 3.42 mmol). The reaction mixture is heated at 60 "С for 19 h. The solvent is removed in vacuo and the residue is purified by KFC (0-15 95, 10945 MNz Meon/udhm) to obtain (3-trifluoromethylphenyl)-amide (g)-5-(6 -(3-carbamoylpyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid. MS (IR) t/2 524.9 (M--1); "H NMR (400 MHz, DMSO -av) 6 parts/million 10.41 (5.1 N), 8.72 (5.1 N), 8.30 (y, 9U-8.84 Hz, 1 N), 8.14 (a , 9U-3.79 Hz, 1 H), 8.10 (5, 1 H), 7.97 (5, 1 H), 7.65 (i,

3-8.08 Hz, 1 N), 7.51 (a, 9U-2.53 Hz, 2 N), 7.16 (yes, 9U-8.84, 2.27 Hz, 1 N), 7 ,12 (5, 1 N), 6,81 (a, 9U-3,54 Hz, 1

H), 3.63 (Bg. 5., 1 H), 3.14 (a, U-7.33 Hz, 1 H), 2.94 (brg. 5., 1 H), 1.99 ( brg. 5., 1 N), 1.25 (a, U-6.06 Hz, 6 N).

Example 96 96-А. (3-Trifluoromethylphenyl)-amide 5-(7-(2-hydroxyethyl)-5,6,7,8-tetrahydropyridoi3,4-4|pyrimidin-4-yloxy|-indole-1-carboxylic acid.

E.S

Go) Z

Rava;

M. U

M

M o nn

S ron

A solution of (3-trifluoromethylphenyl)-amide 5-(5,6,7,8-tetrahydropyridoyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid, compounds of example 33-C (150 mg, 0, 33 mmol), 2-bromomethanol (28 μl, 0.40 mmol) and TEA (0.1 ml, 0.66 ml) in I (3 ml) is heated at 85 °C for 24 h. Then the reaction mixture is concentrated in vacuo and the residue is purified using semi-preparative HPLC (C18; 10-100 95

ACN/H2O with the addition of 0.1 95 MNAOH) and obtain the desired compound. MS (ER) t/2 498.1 (MaА1); "N

NMR (400 MHz, MeOb) 5 ppm 8.38 (5, 1 N), 8.33 (a, 9-8.8 Hz, 1 N), 8.06 (5, 1 N), 7 .93 (y, 9U-3.8 Hz, 1

H), 7.90 (9, 9-8.3 Hz, 1 H), 7.58 (I, 9-81 Hz, 1 H), 7.44 (a, 90-78 Gu, 1 H), 7.41 (a, 9-2.3 Hz, 1 H), 7.11 (aa, 9-9.0, 2.4 Hz, 1 H), 6.74 (a, 9-3.5 Hz , 1 H), 3.81 (Y, 9U-5.8 Hz, 2 H), 3.75 (5, 2 H), 2.96 (5, 4 H), 2.79 (I, 9- 5.8

Hz, 2 N).

The following compounds are obtained by a similar method. 96-8. (3-Trifluoromethylphenyl)-amide (4-fluoro-5-(7-(3-methoxypropyl)-5,6,7,8-tetrahydropyridoyl)3,4-a|pyrimidin-4-yloxy|-2-methylindol-1- carboxylic acid.

E o) o) Z g So

M. 2 U

M

M o nn

Hundred 4-Fluoro-2-methyl-(3-trifluoromethylphenyl)-amide 5-(5,6,7,8-tetrahydro-pyridoyl3,4-a|pyrimidin-4-yloxy)-indole-1-carboxylic acid (250 mg, 0.515 mmol) was dissolved in DMF (5 mL) and 1-bromo-3-methoxypropane (79 mg, 0.515 mmol) and DIPEA (0.11 mL, 0.618 mmol) were added. The reaction mixture is stirred at RT for 72 hours. The reaction mixture is then diluted with EOAc and HO. The organic layer is washed with water and saline, then dried over Ma250O»4, filtered, and concentrated. The residue is purified using KFC (200-100 96 EAs/heptane) and the desired compound is obtained. MS (IER) t/2 557.9 (M.n1).

Example 97 97-А. Tert-butyl ether (g)-3-(methanesulfonyl-(6-11-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy|-pyrimidin-4-ylmethyl)-amino)-pyrrolidin-1- carboxylic acid.

IF)

IS

E Kho 0 o r (c) M.,-0 of x che c) y

To a solution of tert-butyl ether (3-(16-P1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy|-pyrimidin-4-ylmethyl)-amino)-pyrrolidin-1-carboxylic acid (20 mg, 0.033 mmol) in THF (5 ml) at 0 "С add methanesulfonyl chloride (6.0 mg, 0.05 mmol) and TEA (7 mg, 0.066 mmol). After 30 minutes, the mixture is diluted with EtOAc, washed with water, brine, and then the organic layer was dried over Ma»5O:, filtered and the solvent was removed. The residue was purified by KFC (0-10 95.2 M MH3 in Meon/dxMm) and the desired compound was obtained. MS (IR) t /2 6741 (M-y1).

The following compounds are obtained by a similar method. 97-V. (3-Trifluoromethylphenyl)-amide 5-I6-(18, 45)-5-methanesulfonyl-2,5-diazabicyclo(2.2.1|hept-2-ylmethyl)-pyrimidin-4-yloxy|-indole-1-carbon acid

EE

IS

(in)

Zh. about m--yu and- their ef;

H

(c) z

MS (ER) t/2 587.1 (MA1); "H NMR (400 MHz, Meob) b frequency/million 8.61 (a, U-5.05 Hz, 1 H), 8.35 (y, y3-8.84 Hu, 1 H), 8, 06 (5, 1 H), 7.94 (a, 9-3.79 Hz, 1 H), 7.89 (a, 9U-8.08 Hz, 1 H), 7.57 (I, 9U- 8.08 Hz, 1 N), 7.42 (a, 90-1.77 Hz, 1 N), 7.41 - 7.46 (t, 1 N), 7.04 - 7.14 (t, 2 H), 6.74 (y, 2-3.79 Hz, 1 H), 4.63 (5.1 H), 4.26 (5, 1 H), 3.87 (y, 9-5 ,31 Hz, 1 N), 3.61 (5, 1 N), 3.45 (a, U-9.60 Gu, 1 N), 3.24 (da, U-9.35, 2.27 Gu, 1

H), 2.88 (5, C H), 2.82 - 2.91 (t, C H), 1.93 (a, 9-10.61 Hu, 1 H).

Example 98 98-А. Tert-butyl ether (g)-3-(acetyl-/6-(1-(3-trifluoromethylphenyl-carbamoyl)-1H-indol-5-yloxy|-pyrimidin-4-ylmethyl)-amino)-pyrrolidin-1- carboxylic acid. at)

E in U o o 0 i) M schi I

In

Khio) o

To a solution of tert-butyl ether (3-(16-11-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy|-pyrimidin-4-ylmethyl)-amino)-pyrrolidin-1-carboxylic acid (60 mg, 0.10 mmol) in THF (5 ml) at 0 "С, acetyl chloride (12 mg, 0.15 mmol) and TEA (20 mg, 0.2 mmol) are added. After 30 minutes, the mixture is diluted with EIOAc, washed with water, brine and the organic layer dried over Mag5O", filtered and the solvent removed. The residue was purified using KFC (0-10 95, 2 M

MHz in Meon/DxHM) and get the desired compound. MS (IER) t/2 638.1 (M--1).

The following compounds are obtained by a similar method. 98-8. (3-Trifluoromethylphenyl)-amide 5-I(6-(18, 45)-5-acetyl-2,5-diazabicyclo|2.2.1|)hept-2-ylmethyl)-pyrimidin-4-yloxy|-indol- 1-carboxylic acid.

Kf) oo;

M

I am the university

Hu ra o

N SE,

MS (ER) t/2 551.1 (M--1); "H NMR (400 MHz, MeOb) b frequency/million 8.62 (y, 9U-4.55 Hz, 1 H), 8.37 (aa, 9-8.97, 4.93 Hz, 1 H ), 8.07 (5, 1 N), 7.96 (yes, 9-3.79, 2.27 Hz, 1 N), 7.90 (a, 2U-8.84 Hz, 1 N), 7.58 (I, 2-8.08

Hu, 1 H), 7.43 (5, 1 H), 7.44 (1, 9-6.06 Hz, 1 H), 7.12 (aa, O-8.97, 3.79, 2 ,40 Hz, 1 N), 7.07 (a, 9-4.55 Hz, 1

H), 6.76 (Y, 9U-3.41 Hu, 1 H), 4.66 (5, 1 H), 3.86 (v, 2 H), 3.62 (5, 1 H), 3.56 (ad, 9U-10.74, 6.95 Hu, 1 H), 3.24 (ad, 9U-11.49, 1.89 Hz, 1 H), 2.71 (da, O- 13.89, 9.85 Hz, 1 H), 2.08 (5, C H), 1.91 - 2.01 (t, C H).

Example 99 99-А. 5-(6-(1H-Tetrazol-1-yl)umethyl)pyrimidin-4-yloxy)-M-(3-methoxy-5-trifluoromethyl)phenyl)-1H-indole-1-carboxamide.

/

M (c) is 0 U

M

Hmm SE, -that is

M M (in) N

MEM

To a solution of (6-(1-(3-methoxy-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)pyrimidin-4-yl)umethylmethanesulfonate (1.05 mmol) in 4 ml of THF, add a solution 1 H-tetrazole (0.221 g, 3.14 mmol) in 3 mL of DMF, followed by C 52 CO 3 (1.02 g, 3.14 mmol) and Maya (0.472 g, 3.14 mmol). The mixture is stirred at RT for 1 hour. and then diluted with EtOAc, washed with a saturated solution of MaHSOOz (x2), saline solution, and the organic layer was dried over Ma»5O»4. After concentration, the residue is purified using KFC (5-90 90 EOAc/heptane) and two regioisomeric tetrazoles of example 99A and 998 are obtained.

MS (ER) t/2 511.0 (M--1); "H NMR (400 MHz, DMSO-av) b frequency/million 10.35 (5, 1 H), 9.53 (5, 1 H), 8.68 (a, 9-0.8 Hz, 1 H), 8.29 (y, 9-8.8 Hz, 1 H), 8.12 (a, 9-3.8 Hz, 1 H), 7.70 (5, 1 H), 7.60 (I, 9U-2.0 Gu, 1 N), 7.51 (9, 9-2.5 Hz, 1 N), 7.14 (5.2 N), 6.99 - 7.04 (t , 1 H), 6.81 (a, 92-3.5 Hu, 1 H), 5.89 (5, 2 H), 3.86 (5, C H). 99-58. (3-Methoxy -5-trifluoromethylphenyl)-amide of 5-(6-(2H-tetrazol-2-yl)methylpyrimidin-4-yloxy)-indole-1-carboxylic acid. / (6) more) -E

OO MU

M t mm (c) N

M-/

MS (ER) t/2 511.4 (M--1); "H NMR (400 MHz, DMSO-av) b freq./million 10.35 (5.1 H), 9.04 (5.1 H), 8.67 (a, 9-1.0 Hu, 1 H), 8.24 - 8.35 (t, 1 H), 8.08 - 8.17 (t, 1 H), 7.67 - 7.74 (t, 1 H), 7.57 - 7 .63 (t, 1 N), 7.52 (a, 9-2.5 Hz, 1 N), 7.15 - 7.19 (t, 1 N), 7.11 (5.1 N), 7.01 - 7.05 (t, 1 H), 6.79 - 6.83 (t, 1 H), 6.13 (5.2

H), 3.86 (5, C H).

Example 100 (3-Trifluoromethylphenyl)-amide (53-5-16-Kacetylpyrrolidin-3-ylamino)-methyl|-pyrimidin-4-yloxy)-indole-1-carboxylic acid.

E.S o) With shk;

M. 22 M c) rya

MK o nn o

N

Tert-butyl ether carboxylic acid (30 mg, 0.056 mmol) was stirred in solution in DCM (2 mL) and TFA (0.5 mL) overnight. After removal of the solvents, the residue was neutralized with saturated aqueous sodium bicarbonate solution. The mixture was extracted with

Es (Zh). The combined organic layers were washed with water and brine and the organic layer was dried over Mag50O54, filtered and the solvent removed. Then the residue is purified by KFC (0-10 95.2 mol MNz in Meon/DXM) and the desired compound is obtained. MS (IER) t/2 538.9 (M-n1).

Example 101 101-А. (3-Trifluoromethylphenyl)-amide (7)-5-16-((methanesulfonylpyrrolidin-3-ylamino)-methyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid.

E.S

Ge) Z

Su

Mi 2 M 200 th

MU o nn s

M

N

Tert-butyl ether (53)-3-(methanesulfonyl-[6-(11-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy|-pyrimidin-4-ylmethyl)-amino)-pyrrolidin-1- carboxylic acid (12 mg, 0.018 mmol) was stirred in solution in DCM (2 mL) and TFA (0.5 mL) overnight. After removing the solvents, the residue is neutralized with a saturated aqueous solution of sodium bicarbonate. The mixture is extracted using

Es (Zh). The combined organic layers were washed with water and brine and the organic layer was dried over Mag50O54, filtered and the solvent removed. Then the residue is purified using KFC (0-10 95.2 M Mn in MeOH/DHCM) and the desired compound is obtained. MS (ER) t/2 574.8 (M--1).

Example 102 102-А. (5-Tert-butylisoxazol-3-yl)-amide (5)-5-(methyl-6, 7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carbon acid (c) wav; ! and

M H-m

N IF) N

It is obtained by a method similar to that described in example 57. MS (IER) t/2 433.0 (Ma1); "H NMR (400 MHz, Meob) 5 ppm 8.50 (5, 1 H), 8.35 (a, U-8.84 Hz, 1 H), 7.90 (a, 9-3 .79 Hz, 1 N), 7.41 (a, 9-2.27 Hz, 1 N), 7.12 (ad, 9U-8.97, 2.40 Hz, 1 N), 6.73 ( a, 9U-3.79 Hz, 1 N), 6.66 (5, 1 N), 4.70 (d, U-6.48 Hz, 1

Н), 4.10-4.16 (t, 2Н) 1.59 (y, 9-6.57 Hu, З Н) 1.38 (5, 9 Н).

Chiral HPLC (column IA, 40 95 acetonitrile, 60 95 isopropanol) provides the preparation of 2 enantiomers 102-A-1 and 102-A-2: 102-A-1: (5-Tert-butylisoxazol-3-yl)-amide ( -)-5-(methyl-b,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

Ве5.44 min.; MS (IER) t/2 433.0 (M--1); "H NMR (400 MHz, DMSO-av) b frequency/million 8.54 (5, 1 H), 8.30 (a, 9U-9.09 Hz, 1 H), 8.16 (a, 9U -3.79 Hz, 1 H), 7.46 (y, 9-2.27 Hz, 1 H), 7.14 (ad, 9-8.97, 2.40 Hz, 1 H), 6, 76 (a, 9U-3.79 Hz, 1 H), 6.68 (5, 1 H), 4.62 (a, 9U-6.57 Hz, 1 H), 4.12 (a, 9- 2.27 Hz, 1 H), 4.08 (a, 9U-1.52 Hz, 1 H), 1.44 (a, 9-6.57 Hz, C H), 1.34 (5, 9 H). 102-A-2: (5-Tert-butylisoxazol-3-yl)y-amide /(g)-5-methyl-6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidine- 4-yloxy)-indole-1-carboxylic acid.

Ve-6.54 min.; MS (ER) t/ 433.0 (M--1); "H NMR (400 MHz, DMSO-av) 5 ppm 8.54 (5, 1 H), 8.30 (a, 9-8.84 Hz, 1 H), 8.17 (a, 9U -3.79 Hu, 1 H), 7.46 (a, 9-2.27 Hu, 1 H), 7.14 (ad, O-8.97, 2.40 Hu, 1 H), 6, 76 (a, 9-3.79 Gu, 1 H), 6.68 (5, 1 H), 4.62 (a, U-6.65 Hz, 1 H), 4.12 (j, 9- 2.02 Hz, 1 H), 4.08 (a, 9U-1.52 Hz, 1 H), 1.44 (a, 90-6.57 Hu, Z H), 1.34 (5, 9 N).

Example 103 103-А. M-(3-(Isopropylcarbamoyl)-5-(trifluoromethyl)phenyl)-5-(5,6,7,8-tetrahydropyrido3,4- d9|Ipyrimidin-4-yloxy)-1H-indole-1-carboxamide

E.S o) With c;

M. in o

M on -

N

To a solution of 4-(1H-indol-5-yloxy)-5,8-dihydro-6H-pyrido|3,4-4|pyrimidine-7-carboxylic acid tert-butyl ether (0.16 g, 0.437 mmol) in Man (0.105 g, 2.62 mmol) is added to 4 ml of THF at 0 "C.

After stirring for 45 min. add dropwise a solution of phenyl-3-(isopropylcarbamoyl)-5-(trifluoromethyl)phenylcarbamate, the compound of example 13-B (0.224 g, 0.611 mmol) in 2 ml of THF and 1 ml

DMF. The resulting mixture is stirred for 4 hours. and then partitioned between E(Ac) and cold H2O. The aqueous layer was further extracted with EOAcC and the combined organic layers were washed with saturated aqueous Manso"z solution, brine and dried over Ma"5O". After concentration, the residue was purified using KFC (heptane/EtOAc). The resulting product (0.23 g, 0.360 mmol) is then treated with 70 mL of 5095 TFA in DCM at RT for 1 h. After concentration, the residue is purified by semi-preparative HPLC (10-100 95 ACN/H2O with adding 0.1 95 MNAOH) and obtain the desired compound. MS (IR) t/ 539.2 (M--1); "H NMR (400 MHz,

DMSO-dv) 6 ppm 10.49 (Bg. 5., 1 N), 8.54 (y, U-7.8 Hz, 1 N), 8.38 - 8.46 (t, 2 H), 8.25-8.32 (t, 2 H), 8.15 (a, 9-38 Hz, 1 H), 7.98 (5, 1 H), 7.46 (a, 9- 23 Hz, 1 N), 7.13 (aa, 9U-9.0, 2.4 Hz, 1 N), 4.07 - 4.21 (t, 5-13,9,6,9,6, 7.6.7 Hz, 2 N), 3.85 (5.2 N), 3.07 (I, 9-5.8 Hz, 2 N), 2.75 (1, 9-5.7 Hz , 2 H), 1.20 (a, 2-66 Hz, b H).

The following compounds are obtained by a similar method. 103-8.. M-(3-(Methylcarbamoyl)-5-(trifluoromethyl)phenyl)-5-(5,6,7,8-tetrahydropyridoi|3,4-d|pyrimidin-4-yloxy)-1H -indole-1-carboxamide.

Es

A) from the

M. i shchi

M M

M o nH 7

N

MS (ER) t/ 511.1(M--1); "H NMR (400 MHz, DMSO-av) b freq./million 10.50 (bBg. 5., 1 H), 8.73 (ad, 9-40

Hz, 1 N), 8.45 (5, 1 N), 8.40 (5.1 N), 8.24 - 8.32 (t, 2 N), 8.14 (a, 90-3, 8 Hz, 1 H), 7.95 (5, 1 H), 7.46 (a, 9-2.5 Hz, 1 H), 7.13 (ai, U-9.0, 2.4 Hz , 1 H), 6.80 (y, 9-3.5 Hz, 1 H), 3.82 (v, 2 H), 3.03 (y, U-58 Hz, 2 H), 2.83 (y, 9-43 Hz, Z H), 2.72 (I, 9-5.6 Hz, 2 H). 103-6. (3-Isopropylcarbamoyl-5-trifluoromethylphenyl)-amide ()-5-(6-methyl-5,6,7,8-tetrahydropyridoyi3,4-4|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid. still ES vav;

M. and o

M M

M o n -

N

MS (IER) t/2 533.2 (M--1); "H NMR (400 MHz, DMSO-av) 5 ppm 10.49 (bBg. 5., 1 H), 8.53 (a, 9-76

Hz, 1 N), 8.39 - 8.44 (t, 2 N), 8.25 - 8.33 (t, 2 N), 8.14 (y, 9-38 Hz, 1 N), 7 .97 (5, 1 N), 7.45 (a, 9-23 Hz, 1 N), 7.12 (da, 2-9.0, 2.4 Gu, 1 N), 6.79 (y , U-3.5 Hz, 1 N), 4.06 - 4.21 (t, 1 N), 3.81 - 3.97 (t, 2 N), 2.91 - 3.03 (t, 1 H), 2.85 (aa, 9U-16.9, 3.5 Hu, 1 H), 2.29 - 2.39 (t, 1 H), 1.17 - 1.24 (t, 9 N). 103-0. (3-Methylcarbamoyl-5-trifluoromethylphenyl)-amide (g)-5-(b-methyl-5,6,7,8-tetrahydropyridoyl3,4-a|pyrimidin-4-yloxy)-indole-1-carboxylic acid. still EC

SOSO and

M. 2 U

M M

M o nN "SHY

N

MS (IER) t/2 525.2 (M--HT1); "H NMR (400 MHz, DMSO-av) 6 ppm 10.49 (Bk. 5., 1 H), 8.70 - 8.77 (t, 1 H), 8.42 - 8.47 (t, 1 H), 8.44 (ri. 5., 1 H), 8.40 (in, 1 H), 8.30 (a, 9-91 Gu, 1 H), 8.25 - 8 .28 (t, 1 H), 8.14 (ad, U-3.8 Hz, 1 H), 7.93 (Bg. 5., 1 H), 7.45 (a, 9-23 Hz, 1 H), 7.12 (yes, O-8.8, 2.3 Hz, 1 H), 6.79 (a, 9-3.8 Hz, 1 H), 3.80 - 3.95 ( t, 2 H), 2.90 - 3.03 (t, 1 H), 2.80 - 2.89 (t, 4 H), 2.34 (yes, 9-16.3, 10.5 Hz , 1 H), 1.22 (a, 9-6.3 Hz, C H).

Example 104 104-А. Acetic acid 4-(D-Fluoro-2-methyl-1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyrimidin-2-ylmethyl ester).

IS

M. 0 probably.

M. and M

Y-mn (c)

WITH

DBU (5.48 ml, 36.3 mmol) at 0 "C is added dropwise to a suspension of 4-fluoro-2-methyl-1H-indol-5-ol (5.00 g, 30.3 mmol) and 2, of 4-dichloropyrimidine (4.60 g, 30.9 mmol) in SNISM (60 ml). The resulting mixture was heated and stirred at 23 "C for 15 h. The reaction mixture was concentrated and the residue was partitioned between a 1:11 mixture of EOAc-CHNeSig (300 mL) and water (150 mL). The aqueous layer is extracted with EOAc (2x100 ml). The combined organic layers were washed with brine (100 mL), dried (Mag504) and concentrated. the residue is purified by silica gel chromatography (0-100 96 E(Ac/heptane)) and 5-(2-chloropyrimidin-4-yloxy)-4-fluoro-2-methyl-1H-indole is obtained. 1,2-Dibromoethane ( 425 μl, 5.0 mmol) was added to a suspension of powdered zinc (2.83 g, 43.2 mmol) in dry DMF (8 mL). The reaction mixture was heated at 60 °C for 10 min., then cooled to room temperature. TM5CI (500 μl, 4.0 mmol) was added (caution: exothermic reaction) and the resulting mixture was sonicated for 30 min.

The powdered zinc is allowed to settle and the supernatant liquid is removed with a syringe. DMF (8 mL) was added, followed by bromomethyl acetate (2.12 mL, 21.61 mmol). The mixture is stirred at 23 "C for 2.5 hours.

Zinc is allowed to settle, and then a solution of zinc acetoxymethyl bromide at 23 "C is transferred to a solution of 5-(2-chloropyrimidin-4-yloxy)-4-fluoro-2-methyl-1H-indole (2.00 g, 7.20 mmol), of palladium acetate (0.081 g, 0.360 mmol) and 5-rpos (0.355 g, 0.864 mmol) in DMF (10 mL). The resulting mixture was stirred at 237 for 15 h. A saturated aqueous solution of MNACI (100 mL) was added and the mixture was partitioned between EtOAc (150 mL) and water (150 mL). The aqueous layer was extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine (60 mL), dried (Mag25054), and concentrated. The residue was purified by chromatography on silica gel (0-100 96 EtOAc/heptane) and obtain (4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-yl)umethylacetate.

INMOZ5 (lithium hexamethyldisilazane) (1.0 M in THF, 7.68 mL, 7.68 mmol) for 1 min. add to a solution of (4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-yl)methylacetate (1.21 g, 3.84 mmol) and for 40 min. add 1-isocyanato-3-"(trifluoromethyl)benzene (0.70 ml, 5.08 mmol) in THF (40 ml) at -78 "C. Add a saturated aqueous solution of MNACI (100 ml) and water (20 ml) and the mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (30 mL), dried (Mg250»4), and concentrated. The residue was purified by silica gel chromatography (0-100 95 EtOAc/heptane) and obtain 4-I(4-fluoro-2-methyl-1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy|-pyrimidin-2-ylmethyl acetic acid ester. MS (IER) t/2 503, 0 (M--1); "H NMR (400 MHz,

DMSO-dv) b freq./million 10.99 (5, 1 N), 8.68 (a, U-5.81 Hz, 1 N), 8.12 (5, 1 N), 7.92 ( a, 9-7.83 Hz, 1 H), 7.66 (i, 9U-8.08 Hz, 1 H), 7.51-7.55 (t, 2 H), 7.11-7, 18 (t, 2 H), 6.64 (5, 1 H), 5.02 (5, 2 H), 2.59 (5, Z H), 1.88 (5,

ZN). 104-8. (3-Trifluoromethylphenyl)-amide of 4-fluoro-5-(2-hydroxymethylpyrimidin-4-yloxy)-2-methylindole-1-carboxylic acid.

IS

M. o shi S o"

M. and M

Y-mn (c) as

Potassium carbonate (289 mg, 2.09 mmol) was added to a solution of 4-14-fluoro-2-methyl-1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-pyrimidin-2-ylmethyl acetic acid (1.05 g, 2.09 mmol) in Meon (40 ml) at 23 "C. The resulting mixture was stirred at 23 "C for 1 hour. A saturated aqueous solution of MNaACI (50 ml) and water (20 ml) are added, and the mixture is extracted with EOAc (3x50 ml). The organic layers were combined, washed with brine (30 ml), dried (Ma»5O54) and concentrated. The residue is purified by chromatography on silica gel (10-100 96 EIOAc/heptane) and (3-trifluoromethylphenyl)-amide 4-fluoro-5-(2-hydroxymethylpyrimidine-

4-yloxy)-2-methylindole-1-carboxylic acid. MS (IER) t/2 461.0 (M--1); "H NMR (400 MHz, DMSO-av) b freq./million 11.02 (5, 1 H), 8.69 (a, 9U-5.56 Hz, 1 H), 8.12 (5.1 H), 7.91 (5, 1 H), 7.66 (i, U-7.96 Hz, 1 H), 7.52 (I, 9U-8.34 Hz, 2 H), 7.17 (aa, 2-8.84, 7.83 Hz, 1 H), 7.05 (a, U-5.56 Hz, 1 H), 6.63 (5, 1 H), 5.14 (I , 2-6.19 Hu, 1 H), 4.38 (9, 2-6.32 Hz, 2 H), 2.59 (5, C H).

Example 105 105-А. 4-fluoro-5-2-(2-hydroxyethylamino)-methyl|-pyrimidin-4-yloxy)-2-methylindole-1-carboxylic acid (3-trifluoromethylphenyl)-amide.

IS

NU and M. i

M. Z

M.S.O.

Mah M

AH-kn (c)

Methanesulfonyl chloride (0.046 mL, 0.586 mmol) was added to a solution of 4-fluoro-5-(2-hydroxymethylpyrimidin-4-yloxy)-2-methylindole-1-carboxylic acid (3-trifluoromethylphenyl)-amide (180 mg, 0.391 mmol) and EizM (0.109 mL, 0.782 mmol) in SNeoSi (5 mL). After 10 min, ethanolamine (0.236 mL, 3.91 mmol) was added and the resulting mixture was heated and stirred at 23 °C for 4 h. Meon (2 ml) was added and the reaction mixture was stirred for another 15 h. The reaction mixture was partitioned between EOAc (40 mL) and water (40 mL). The aqueous layer is extracted using

EUAs (2x40 ml). The combined organic layers were washed with brine (30 mL), dried (Mag5O4) and concentrated. The residue is purified by chromatography on silica gel (0-10 925 MEeEON/СНеСиг) to obtain (3-trifluoromethylphenyl)-amide 4-fluoro-5-12-K(2-hydroxyethylamino)-methyl|-pyrimidin-4-yloxy)- 2-methylindole-1-carboxylic acid. MS (ER) t/2 504.2 (M-e1); "H NMR (400 MHz, meob) b frequency/million 8.60 (a, U-5.81 Hz, 1 H), 8.07 (5, 1 H), 7.86 (5, 1 H) , 7.57 - 7.62 (t, 1 H), 7.46 - 7.51 (t, 2 H), 7.09 (yes, O-8.84, 7.33 Hz, 1 H), 6.98 (y, 9U-5.81 Hz, 1 N), 6.54 (5, 1 N), 3.82 (5.2 N), 3.55 - 3.58 (t, 2 N) , 2.65 - 2.71 (t, 2 H), 2.62 (5, C H).

The following compounds are obtained by a similar method. 105-8. (3-Trifluoromethylphenyl)-amide of 4-fluoro-2-methyl-5-(2-methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid.

IS

M. 0

НЗСсНнМ in:

Ko et x st»

M 2 M

X-kn (c)

MS (ER) t/2 474.0 (M--1); "H NMR (400 MHz, Meor) b frequency/million 8.67 (y, 9U-5.81 Hz, 1 H), 8.08 (5, 1

H), 7.67 (y, 9-8.34 Hz, 1 H), 7.58 - 7.62 (t, 1 H), 7.47 - 7.53 (t, 2 H), 7, 05 - 7.11 (t, 2 H), 6.53 (5.1 H), 4.09 (5, 2 H), 2.63 (5, Z H), 2.62 (5, Z H ).

Example 106 106-А. (3-Trifluoromethylphenyl)-amide /4-fluoro-5-(2-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methylindole-1-carboxylic acid.

IS

M. o

Нз3СО»5 ве зсоО»87 р In Art

M. and M

Y-mn (c)

Methanesulfonyl chloride (0.046 mL, 0.586 mmol) was added to a solution of 4-fluoro-5-(2-hydroxymethylpyrimidin-4-yloxy)-2-methylindole-1-carboxylic acid (3-trifluoromethylphenyl)-amide (180 mg, 0.391 mmol) and EizM (0.109 mL, 0.782 mmol) in SNeoSi (5 mL). After 10 min, methanol was added, followed by sodium methanesulfinate (798 mg, 7.82 mmol). The resulting mixture was heated and stirred at 23 °C for 14 hours The mixture was concentrated and the residue was taken up in DMF (5 mL).

The resulting mixture is stirred at 23 "C for 24 hours, then partitioned between EAs (40 ml) and water (40 ml). The aqueous layer is extracted with EAs (2 x 40 ml). The combined organic layers are washed with saline solution (20 ml ), dried (Mag25054) and concentrated. The residue was purified by chromatography on silica gel (0-10095 E(OAc/heptane)) to obtain (3-trifluoromethylphenyl)-amide 4-fluoro-5-(2-methanesulfonylmethylpyrimidin-4-yloxy) -2-methylindole-1-carboxylic acid. MS (ER) t/2 474.0 (M--1); "H NMR (400 MHz, DMSO-dv) b parts/million 10.98 (5, 1 H), 8.76 (a, 9-5.81 Hz, 1 H), 8.12 (5, 1 H), 7.91 (a, 9-8.34 Gu, 1 H), 7.64 - 7.69 (t, 1 H), 7.53 (y, U-8.84 Hz, 2

H), 7.18-7.25 (t, 2 H), 6.63 (5, 1 H), 4.55 (5, 2 H), 2.97 (5, C H), 2.59 (c, Z H).

Example 107 107-А. Tert-butyl-4-(1-(3-(hydroxymethyl)-5-(trifluoromethyl)phenyl-carbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyridoy3,4-4|pyrimidine-7(8H )-carboxylate.

M.O EzS vav;

M. U

M On

X- and

To a solution of tert-butyl-4-(1-(3-(tert-butyldimethylsilyloxy)methyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyridoyi3,4-d|pyrimidine -7(8H)-carboxylate (0.252 g, 0.361 mmol) in 6 ml of THF and 14 ml of water, add 26 ml of acetic acid. The mixture is heated at 32 "C for 5 hours, then the reaction mixture is diluted with EtOAc, washed with a mixture of water/pyridine, saturated sodium bicarbonate solution, saline solution and dried over sodium sulfate, concentrated and the desired compound is obtained. MS (IER) t/ 2 584.2 (M-n1). 107-8. Tert-butyl-4-(1-(3-(methylsulfonyloxy)methyl)-5-(trifluoromethyl)-phenylcarbamoyl)-1H-indol-5-yloxy) -5,6-dihydropyridoy3,4-4|pyrimidine-7(8H)-carboxylate mo ES

SOYU Z.

M. 2 M

Hmm oh oh-!

M o nn 5-

Ho o

X-

To o solution / tert-butyl-4-(1-(3-(hydroxymethyl)-5-(trifluoromethyl)phenyl-carbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyridoyi3,4-4|pyrimidine -7(8H)-carboxylate (0.211 g, 0.361 mmol) in b ml of DCM with

Methanesulfonyl chloride (0.037 ml, 0.469 mmol) is added to DIPEA (0.19 ml, 1.08 mmol) at 0 °C, and the reaction mixture is stirred for 3 h. Then the reaction mixture is diluted with

EtOAc, washed with saturated sodium bicarbonate solution, brine, and the organic layer was dried over sodium sulfate. Concentration provides a mixture of the desired compound and tert-butyl-4-(1-(3-(chloromethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyridoy3,4-d| pyrimidine-7(8H)-carboxylate (3:7), which is used in the next stage. 107-6. M-(3-(Isopropylamino)methyl)-5-"(trifluoromethyl)phenyl)-5-(5,6,7,8-tetrahydropyridoyi3,4- d9|Ipyrimidin-4-yloxy)-1H-indole-1 -carboxamide.

IF) o) From the seam;

Mu U

M M

M o H -

N

Isopropylamine (0.06 ml, 0.680 mmol), then sodium iodide (0.1 g, 0.68 mmol) is added to a solution of the mixture obtained above (0.15 g, 0.227 mmol) in 3 ml of DCM. In 45 minutes. LC-MS shows that tert-butyl-4-(1-(3-(methylsulfonyloxy)methyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-

dihydropyridoyi3,4-d|pyrimidine-7(8H)-carboxylate turned into the desired product and remained tert-butyl-4-(1-(3-(chloromethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indole-5- yloxy)-5,6-dihydropyridoy3,4-d9|Ipyrimidine-7(8H)-carboxylate. Three ml (0.227 mmol) of isopropylamine is added to the reaction mixture, then

Ma! (0.1 g, 0.68 mmol) and the mixture is heated at 45 °C for 2 h. The solvent is then removed and the residue is diluted with EtOAc, washed with H2O, brine, and the organic layer is dried over Mag250O5. After concentration, the residue is purified with the help of KFC (25-100 95 EOAc/heptane). This product is then treated with 60 ml of a mixture of 50 96 TFA/DKM at CT for 1.5 h. After concentration, the residue is purified using a semi-preparative

HPLC (0-18; 10-100 95 ACN/HgO with the addition of 0.1 95 MNAOH) and obtain the desired compound. MS (IER) t/2 525.2 (M-1); "H NMR (400 MHz, DMSO-av) 5 ppm 10.33 (5, 1 N), 8.40 (5, 1 N), 8.27 (a, 9-88 Hz, 1 N) , 8.13 (9, 9-3.8 Hz, 1 N), 7.95 (y, 9-15.2 Hz, 2 N), 7.38 - 7.52 (t, 2 N), 7 ,11 (ad, 9-9.0, 2.4 Hz, 1 N), 6.78 (a, 9-3.8 Gu, 1 N), 3.81 (a, U-7.6 Hz, 4 H), 3.03 (1, 9-5.8 Hz, 2 H), 2.68 - 2.79 (t, Z H), 1.03 (a, 9-61

Hz, 6 N).

Example 108 108-А. (3-Trifluoromethylphenyl)-amide 5-(2-azidomethylpyridin-4-yloxy)-indole-1-carboxylic acid su

M. 22 oyu

Ma o nn

A mixture of methanesulfonic acid (505 mg, 1.03 mmol) and sodium azide (201 mg, 3.12 mmol) in DMSO (5 ml) is heated at 80 °C for 2 h. Then the mixture is diluted with DCM (100 ml) and water.

The organic layer is additionally washed with saline solution and then dried over anhydrous Mag250O.

After concentration, the residue is purified using KFC (20-90 956 EAs/heptane) and the desired compound is obtained. MS (IER) t/2 453.1 (M--1). 108-8. (3-Trifluoromethylphenyl)-amide 5-(2-aminomethylpyridin-4-yloxy)-indole-1-carboxylic acid su i i Co,

(3-Trifluoromethylphenyl)-amide 5-(2-azidomethylpyridin-4-yloxy)-indole-1-carboxylic acid (165 mg, 0.36 mmol) was dissolved in THF (5 ml) at 0 "С and add lithium aluminum hydride (0.55 mL, 0.55 mmol, 1.0 M solution in THF).After 2 h, the reaction is quenched with water, then extracted with EACs.

The organic layer is washed with a saturated aqueous solution of MNASiCl and then dried over anhydrous

Mag5O". After concentration, the residue is purified by means of semi-preparative HPLC (C18; 10-100 96 ACN/H2HO with the addition of 0.1 95 MNAOH) and the desired compound is obtained. MS (ER) t/2 427.1 (M-nH1);

NMR NMR (400 MHz, DMSO-av) 5 parts/million 8.29 - 8.39 (t, 2 N), 8.15 (9, 9U-3.8 Hz, 1 N), 8, 09 (5, 1 H), 7.97 (a, 9-81 Hz, 1 H), 7.64 (I, U-8.0 Hz, 1 H), 7.50 (a, 9-7, 6 Hu, 1 H), 7.45 (a, 9-2.5 Hz, 1 H), 7.12 (aa, U-8.8, 2.5 Hz, 1 H), 7.00 (5, 1 H), 6.81 (a, 9U-3.3 Gu, 1 H), 6.76 (a, 9-3.5 Hz, 1 H), 3.76 (5.2 H).

Example 109 109-А. 4-(11-(3-cyano-5-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-5,8-dihydro-6bH-pyrido|3,4-d|pyrimidine-7-carboxylic acid tert-butyl ether

M. O ke; waf;

Moss in SM

M (c); their oo

4-(1H-indol-5-yloxy)-5,8-dihydro-6H-pyridoI3,4-4|pyrimidine-7-carboxylic acid tert-butyl ether, compound of example 31-E (140 mg, 0.38 mmol ) is dissolved in THF (5 mL) and Mann (31 mg, 0.76 mmol, 60 95 in mineral oil) is added, then (3-cyano-5-trifluoromethylphenyl)-carbamic acid phenyl ether (428 mg, 1.15 mmm). After 24 hours the reaction mixture is concentrated and then partitioned between DCM and water. The crude residue is purified using KFC (5-

90 95 EOAc/heptane) and obtain the desired compound. MS (IER) t/» 579.2 (M--1). 109-0.. (3-Cyano-5-trifluoromethylphenyl)-amide of 5-(5,6,7,8-tetrahydro-pyrido|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid .

E.S

IF) Z

CO

M. 22 M SM

hmm

M o nn

N

Solution of tert-butyl ether 4-(11-(3-cyano-o-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy|- 5,8-dihydro-6H-pyridoi|3,4-4|Ipyrimidine- of 7-carboxylic acid (132 mg, 0.28 mmol) in DCM (2 mL) and TFA (2 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and purified by semi-preparative HPLC (C18; 10-100 95 ACN/HgO with the addition of 0.1 96 MNAOH) and obtain the desired compound. MS (IER) t/g2 479.0 (M--1); "H NMR (400 MHz, DMSO-dv) b parts/million 8.38 - 8.42 (t, 2 H), 8.35 (5, 1 H), 8.28 (y, 9U-8.8 Hz, 1 H), 8.07 - 8.12 (t , 2 H), 7.47 (a, 9-23 Hz, 1 H), 7.14 (da, 90-88, 2.3 Gu, 1 H), 6.83 (y, 2-3.3 Hz, 1 N), 3.85 (5, 2 N), 3.06 (I, 9U-5.8 Hz, 2 N), 2.74 (i, 3-5.7 Hz, 2 N).

The following compounds are obtained by a similar method. 109-E. (3-Methoxy-5-trifluoromethylphenyl)-amide 5-(5,6,7,8-tetrahydro-pyrido|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

E.S

IF) Z

There is If; /

Mo u o

M

M o nn

N

MS (IER) t/2 484.3 (М-А-1); "H NMR (400 MHz, DMSO-av) b freq./million 10.33 (bBg. 5., 1 H), 8.40 (5.1 H), 8.26 (a, 9-9.1 Gu, 1 H), 8.10 (a, 9U-3.5 Hz, 1 H), 7.60 (5, 1 H), 7.45 (5, 1 H), 7.12 (a, 9 -8.8 Hz, 1 N), 7.02 (5, 1

H), 6.79 (a, 9-3.5 Hz, 1 H), 3.86 (5, Z H), 3.82 (5, 2 H), 3.03 (I, U-5, 8 Hz, 2 N), 2.67 - 2.76 (t, 2 N).

Example 110 110-А. (4-Fluoro-3-trifluoromethylphenyl)-amide 5-(6-(4-bromobutyrylamino)-methyl|-pyrimidin-4-yloxy)-indole-1-carboxylic acid.

Eh heh

N with 9 ud

IF) Me M

And /

ME o 5-(4-Fluoro-3-trifluoromethylphenyl)-amide b-aminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (52.5 mg, 0.117 mmol) is dissolved in DCM (5 ml) at 0 "С . DIPEA (0.025 mL, 0.143 mmol) was added followed by 4-bromobutyryl chloride (0.020 mL, 0.172 mmol). The reaction mixture was stirred for a few minutes and then diluted with ethyl acetate and washed with water. The organic layer was separated, dried and concentrated to give the title compound. MS (IER) t/2 595.6 (M.n1). 110-8. (4-Fluoro-3-trifluoromethylphenyl)-amide 5-(6-(2-oxopyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy |- indole-1-carboxylic acid.

EE is

M. O. U

M M

And Y

M o (4-Fluoro-3-trifluoromethylphenyl)-amide 5-16-(4-bromobutyrylamino)-methyl|-pyrimidin-4-yloxy-indole-1-carboxylic acid (0.353 g, 0.595 mmol) is dissolved in 10 ml of THF and cooled to 0 "s.

Sodium hydride (63 mg, 1.5 mmol, 60 95 in mineral oil) was added and the reaction mixture was allowed to warm to room temperature overnight. The reaction is quenched with water and diluted with ethyl acetate. The organic layer is separated, dried and concentrated, and the residue is purified by means of semi-preparative HPLC (C18; 20-100 96 ACN/H2O with the addition of 0.1 to TFA) and the desired compound is obtained. MS (IER) t/2 514.9 (M--1); "H NMR (400 MHz, DMSO-av) 5 ppm 10.40 (5, 1 H), 8.68 (a, 9-1.01 Gu, 1 H), 8.28 (a, 9 -9.09 Hz, 1 N), 8.09 - 8.12 (t, 2 N), 7.99 - 8.03 (t, 1 N), 7.57 (I, 9U-9.85 Hz , 1

NO, 7.49 (y, 9-2.27 Hz, 1 H), 7.15 (yes, 9U-8.97, 2.40 Gu, 1 H), 6.94 (y, 9U-1, 01 Hz, 1 N), 6.81 (a, 9U-3.79 Hz, 1

H), 4.45 (5, 2 H), 3.42 (I, 9U-6.95 Hz, 2 H), 2.29 - 2.34 (t, C H), 2.00 (I, 9U-7.58 Hz, 2 N).

Example 111 111-A.. (2-Methylbenzofuran-5-yl)-amide of 5-(6,7-dihydro-5H-pyrrolo|3,4-4|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid . (c) with IF; 7

M. M

M Hmm

N IF) N

Tert-butyl-4-(1H-indol-5-yloxy)-5H-pyrrolo|3,4-4|pyrimidine-6(7H)-carboxylate (152.2 mg, 0.432 mmol) was suspended in THF (5 mL) , purged with nitrogen, and cooled to 0 "C. Add Mann (33 mg, 0.825 mmol, 6095 in mineral oil) and stir the mixture for 10 min. Add undiluted phenyl 2-methylbenzofuran-5-ylcarbamate (280 mg, 1.048 mmol) and the reaction the mixture was stirred at room temperature overnight. The reaction mixture was cooled in an ice bath and the reaction was quenched with saturated ammonium chloride solution (100 mL). The solution was then diluted with ethyl acetate and the product was extracted (2 x 100 mL ethyl acetate). The organic layers were combined, dried, and concentrated and a brown oil is obtained, which is dissolved in 10 mL of DCM and cooled in an ice bath and then 10 mL of TFA is added. The TFA is removed and ethyl acetate is added to the residue and ammonium hydroxide is added to neutralize the remaining TFA. The solution is concentrated and dissolved in DMSO and purified by semipreparative HPLC (C18; 20-100 95 ACN/NgO with by adding 0.1 95 TFA) and obtain (2-methylbenzofuran-5-yl)-amide 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indol-1- carboxylic acid. MS (IER) t/2 426.0 (M--1); "H NMR (400 MHz, Meob) b freq./million 8.53 (5, 1 H), 8.30 (a, 9-8.84 Hz, 1 H), 8.15 - 8.20 (t , 1 H), 7.88 - 7.92 (t, 1 H), 7.58 (daa, 9U-6.13, 3.98, 2.27 Hz, 1 H), 7.39 - 7, 46 (t, 2 H), 7.12 (da, 9-9.09, 2.02 Gu, 1 H), 6.74 (a, 9-3.79 Hz, 1 H), 6.46 ( 5, 1 H), 4.19 (a, 9-9.35

Hz, 4 H), 2.45 (5, C H).

The following compounds are obtained by a similar method. 111-8. (1-Methyl-1H-indol-4-yl)-amide 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid. (6) wav;

M. Mak mshe

N (6) N

MS (ER) t/2 425.0 (M--1); "H NMR (400 MHz, Meor) b frequency/million 8.54 (5.1 H), 8.30 (a, 9U-9.09 Hz, 1

H), 8.00 (y, 9U-3.54 Hz, 1 H), 7.44 (a, 2-2.53 Hz, 1 H), 7.19 - 7.33 (t, 4 H) , 7.11 (aa, 9-9.09, 2.27 Hz, 1 H), 6.75 (a, 9-3.79 Hz, 1 H), 6.55 (a, 9-3.28 Hz, 1 H), 4.19 (a, 9-1.52 Hz, 4 H), 3.84 (5, C H).

Example 112 112-А. 16-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-ylmethyl|-methylamine.

IS

Mag with 7 So-

Mo M

N

SH) 6-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-ylmethyl ether of methanesulfonic acid (2.5 g, 8.78 mmol) at RT for 24 h. stirred in DCM (40.0 mL) with a 1 M solution of methylamine in THF (4.39 mL, 8.78 mmol). The reaction mixture is diluted with HgO and EIOAc. The organic layer is washed with saline, dried over Mag25O4, filtered and purified using

KFC by elution first with 10-100 95 EIHUAcC in heptanes, then with 0-96 Meon with the addition of MH3 in EAs and obtain the desired compound. MS (IER) t/2 287.2 (Ma1); /N

NMR (400 MHz, Meob) 5 ppm 8.63 (a, 9U-1.01 Hu, 1 H), 7.11 (a, 9-8.59 Hz, 1 H), 7.02 ( 5, 1 H), 6.85

(ad, 9U-8.59, 7.33 Hz, 1 H), 6.23 (5, 1 H), 3.81 (5, 2 H), 2.41(5, C H), 2, 44 (5, Z H). 112-8. Tert-butyl ester of 16-(4-fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-ylmethyl|- methylcarbamic acid.

IS

Mao eu'So-

M M

N

H

J

BOC2O ( 0.551 mL, 2.37 mmol) and TEA (0.33 mL, 2.37 mmol). The mixture is stirred at room temperature for 18 hours, then a saturated aqueous solution of Manso, water and 150 ml of EA are added. The aqueous phase is additionally extracted with 50 ml of EOAc. The organic layers were combined, washed with saline and dried over NaCl. After concentration, the residue is purified using KFC (0-5 906 MeoOnH in DCM) and the desired compound is obtained. MS (ER) t/2 385.1 (M.n1). 112-S. Tert-butyl ether 16-(11-(5-tert-butylisoxazol-3-ylcarbamoyl)-4-fluoro-2-methyl-1H-indol-

B-yloxy|-pyrimidin-4-ylmethyl)-methylcarbamic acid.

IS

M. U

MN

Km o

What?

J I"

To a solution of 16-(4-fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-ylmethyl|-methylcarbamic acid tert-butyl ether (275 mg, 0.712 mmol) in THF (7 mL) in an atmosphere nitrogen at 0 "C is added

Mann (85 mg, 2.13 mmol). The resulting mixture is stirred for 2 hours. Then (5-tert-butylisoxazol-3-yl)y-carbamic acid phenyl ether (370 mg, 1.42 mmol) was added to this mixture. The resulting mixture is allowed to heat up to room temperature and stirred for 18 hours. Then the reaction is stopped with a saturated aqueous solution of ammonium chloride. The aqueous phase is extracted with EAs (2x). The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, concentrated and purified with KFC (0-70 90 EtOAc/heptane) to give the desired compound.

MS (ER) t/2 553.1 (M-H1). 112-0. 4-Fluoro-2-methyl-(5-tert-butylisoxazol-3-yl)-amide of 5-(b-methylamino-methylpyrimidin-4-yloxy)-indole-1-carboxylic acid.

IS

M M

2-book

Hmm o

Sh

In o

To a solution of 16-(1-(5-tert-butylisoxazol-3-ylcarbamoyl)-4-fluoro-2-methyl-1H-indol-5-yloxy|-pyrimidin-4-ylmethyl)-methyl-carbamino tert-butyl ether acid (.25 g, 0.452 mmol) in DCM (10 ml) add TFA (1.5 ml). After three hours the solvent is removed using a rotary evaporator and the residue is diluted with DCM and water. For neutralization, a concentrated solution of MNAOH is added, and the aqueous phase is extracted twice with DCM. The organic layers are washed with saline, dried over Ma»5O54 and concentrated to obtain the desired compound. MS (ER) t/2 453.1 (M--1); "H NMR (400 MHz, DMSO-av) 6 ppm 8.64 (y, 9U-1.01 Hz, 1 H), 7.52 (y, 9U-8.59 Hz, 1 H),

7.19 (5, 1H) 7.15 (yes, 9U-8.72, 7.71 Hz, 1H), 6.65 (5, 1H), 6.58 (5, 1H), 3 .76 (5, 2 H), 2.56 (5, Z H), 2.33 (5, Z

N), 1.34 (5.9 N).

Example 113

I5-(1-Methylcyclopropyl)-1H-pyrazol-3-yl|-amide 5-(7-methyl-5,6,7,8-tetrahydropyrido|3,4-4|pyrimidin-4-yloxy)-indole -1-carboxylic acid. wav and

M. mo 1 LN umy M

And about nn

It is obtained from the compound of example 54-0) by a method similar to that described in example 63-A. MS (IER) t/2 444.3 (M--1); "H NMR (400 MHz, DMSO-av) 5 ppm 12.13 (Bg. 5., 1 H), 10.56 (5, 1 H), 8.42 (5, 1 H), 8 .29 (a, 9-91 Hz, 1 N), 8.16 (a, 9-3.5 Hz, 1 N), 7.42 (a, 9-23 Hz, 1 N), 7.09 ( aa, U-9.0, 2.4 Hz, 1 N), 6.70 (а, 9-3.5 Hz, 1 N), 6.29 (5, 1 N), 3.51 (5, 2 N), 2.84 (1, 90-5.7 Hz, 2 N), 2.66 - 2.76 (t, 2 N), 2.40 (5, 3 N), 1.41 (5 .3 N), 0.89 - 0.97 (t, 2 N), 0.74 - 0.83 (t, 2 N).

Example 114

15-(1-Methylcyclopropyl)-1H-pyrazole-3-yl1-amide. 5-(7-ethyl-5,6,7,8-tetrahydropyridoyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid. vva; and

M. my LN minds M

D o nn

It is obtained from the compound of example 54-0) by a method similar to that described in example 37-A. MS (ER) t/2 458.4 (M--1); "H NMR (400 MHz, DMSOO-av) 5 ppm 12.13 (5.1 H), 10.55 (5.1 H), 8.42 (5.1

H), 8.29 (a, 9-8.8 Hz, 1 H), 8.16 (a, 9U-3.5 Hz, 1 H), 7.42 (a, 9U-2.3 Hz, 1 H), 7.09 (da, U-8.8, 2.3 Hz, 1 H), 6.70 (a, 9-3.5 Gu, 1 H), 6.30 (a, 9U- 1.8 Gu, 1 H), 3.56 (5, 2 H), 2.80 - 2.88 (t, 2 H), 2.73 - 2.80 (t, 2 H), 2.58 (a, 9-7.3 Hz, 2 H), 1.41 (5, C H), 1.12 (1, 90-7.2 Hz, C H), 0.89 -0.96 (t , 2 N), 0.75 -0.81 (t, 2 N).

Example 115 115-А. (3-Trifluoromethylphenyl)-amide (g)-5-17-(2-hydroxyethyl)-6-methyl-5,6,7,8-tetrahydropyridoi3,4-a|pyrimidin-4-yloxy|-indole-1- carboxylic acid.

Che ES vav;

M. 2 in ts (in) N on

Methyl bromoacetate (0.15 mL, 1.58 mmol) was added to a solution of (3-trifluoromethylphenyl)-amide 5-(6-methyl-5,6,7,8-tetrahydropyridoyi3,4-4|pyrimidin-4-yloxy)- of indole-1-carboxylic acid, compound of example 52-88 (0.370 g, 0.792 mmol) and TEA (0.44 mL, 3.17 mmol) in ACN (10 mL). The solution is stirred overnight. Then the solution is concentrated and the residue is purified using KFC (30-100 95

EtOAc/heptane) and obtain the methyl ether (6b-methyl-4-(1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-5,8-dihydro-6H-pyridoi3,4-4|pyrimidine- 7-yl)-acetic acid.

PAN: (0.46 ml, 1.0 M THF) is added to a solution of methyl ether /b-methyl-4-(1-(3-trifluoromethylphenylcarbamoyl)-1H-indol-5-yloxy|-5,8-dihydro -6H-pyridoyi3,4-4|pyrimidin-7-yl-acetic acid (0.125 g, 0.232 mmol) in THF (5 mL). After 0.5 h, the excess of HIAIN is removed by adding a saturated aqueous solution of MNACI. The workup is carried out saturated aqueous solution of MNACI and DCM (25 ml each). The residue is then purified by semi-preparative HPLC to obtain (3-trifluoromethylphenyl)-amide 5-I(7-(2-hydroxyethyl)-6-methyl-5,6,7 . ) b freq./million 8.42 (5, 1 N), 8.30 (a, U-8.6 Hz, 1 N), 8.11 (a, 9U-3.5 Hz, 1 N), 8.09 (5.1 N), 7.94 (a, 9-8.3 Hz,

1 H), 7.57 - 7.65 (t, 1 H), 7.41 - 7.46 (t, 2 H), 7.11 (aa, 9-9.0, 2.4 Hz, 1 H), 6.72 - 6.78 (t, 1 H), 4.47 (i, 9-5.4 Hz, 1 H), 3.75 (5, 2 H), 3.57 (4, 9-61 Hz, 2 H), 3.12 - 3.22 (t, 1 H), 2.88 - 3.00 (t, 1 H), 2.54 - 2.76 (t, Z H) , 1.10 (a, 9-66 Hz, Z H).

The following compounds are obtained by a similar method. 115-8. (5-Cyclopropylisoxazol-3-yl)-amide 5-(5)-7-(2-hydroxyethyl)-6-methyl-5,6,7,8-tetrahydropyridoyi3,4-4|pyrimidin-4-yloxy|- indole-1-carboxylic acid.

There is a | T U and ! and

M. mm 1 6

M"

To and what he

MS (ER) t/2 475.1 (M--1); "H NMR (400 MHz, DMSO-av) 6 ppm 11.21 (5.1 N), 8.42 (5.1 N), 8.27 (a, U-8.84 Hz, 1 H), 8.15 (a, 9U-3.79 Hz, 1 H), 7.44 (y, 9-2.27 Hz, 1 H), 7.13 (ad, 9U-8.97, 2 ,40 Hz, 1 H), 6.74 (a, 9-3.79 Gu, 1 H), 6.65 (5, 1 H), 4.47 (I, 95.43 Hz, 1 H), 3.74 (5, 2 H), 3.57 (a, 96.06 Hz, 2 H), 3.13 - 3.19 (t, 1 H), 2.93 (da, 9U-16.67 , 5.05 Hz, 1 N), 2.60 - 2.73 (t, 2 N), 2.56 (aa, 9U-17.31, 5.68 Hz, 1 N), 2.17 (8 , 98.49, 5.02 Hz, 1 N), 1.05--1.11 (t, 5 N). 0.92-0.97 (t, 2 N).

Example 116 116-А. 1H-Indol-5-yl ester of diethylcarbamic acid

N

Her S

5-Hydroxyindole (4.4 g, 33.0 mmol) was placed in pyridine (31 mL) and TEA (5.8 mL, 41.6 mmol) was added. Undiluted diethylcarbamoyl chloride (7 mL, 55.2 mmol) was added and the resulting solution was stirred at room temperature for 4 h. The reaction is then quenched with ice water and diluted with ethyl acetate. The layers are separated and the aqueous layer is additionally extracted using

EtOAc (2x250 mL) and organic layers were combined, dried (sodium sulfate) and concentrated to give an orange oil, which was absorbed on silica and purified by HPLC (0-50 95 ethyl acetate:heptanes) to give the desired compound. MS (IER) t/2 233.28 (M--1). 116-8. Diethylcarbamic acid 1-(tert-butyldimethylsilanyl)-1H-indol-5-yl ester.

Diethylcarbamic acid 1H-indol-5-yl ether (5.72 g, 24.6 mmol) is dissolved in THF (200 ml) and cooled to 0 °C. The flask is purged with nitrogen and then 60 95 Mann (1.1 g, 27.5 mmol) and the mixture was stirred in an ice bath for 30 min. Then TVOM5SII (0.210 g, 1.39 mmol) was added and the reaction mixture was stirred overnight (14 h). The reaction was quenched. saturated ammonium chloride solution and the mixture is diluted with ethyl acetate and water. The organic layer is separated, dried (sodium sulfate) and concentrated to obtain the desired compound in the form of an oil, which is used without further purification. MS (ER) t/2 347.21 (M-n1 ). 116-60. 1-"tert-butyldimethylsilanyl)-4-chloro-1H-indol-5-yl ether of diethylcarbamic acid.

ZV. about M

AI

Ca 1-(tert-butyldimethylsilanyl)-1H-indol-5-yl ether of diethylcarbamic acid (9.26 g, 26.7 mmol) is dissolved in THF (250 ml), purged with nitrogen and cooled to -78 "C. Then add

TMEDA (tetramethylethylenediamine) (5 mL, 33.1 mmol), followed by t-butyllithium (24.8 mL, 34.7 mmol) and the reaction mixture was stirred for 30 min. During 10 minutes. hexachloroethane (12.73 g, 53.8 mmol) in 50 ml of THF was added to the reaction mixture. The reaction mixture was allowed to warm to room temperature overnight (15 h). The reaction mixture is cooled with an ice bath and a saturated solution of ammonium chloride (aqueous) (150 ml) is added. The mixture is then extracted with ethyl acetate, dried (sodium sulfate) and concentrated to obtain the desired compound as an oil, which is used without further purification. MS (IER) t/: 381.1 (M--1). 116-0. 4-Chloro-1H-indole-5-ol.

N

M in; but

SI

Diethylcarbamic acid 1-"tert-butyldimethylsilanyl)-4-chloro-1H-indol-5-yl ether (12.2 g, 31.9 mmol) is dissolved in diethyl ether (250 ml) and AHL (lithium aluminum hydride ( 1.21 g, 31.9 mmol) and heated at 40 °C for 5 h. The reaction mixture was cooled to room temperature, placed in an ice bath, and the reaction was stopped with 0.5 N Mahon (aqueous solution). diluted with ethyl acetate and the organic layer separated, dried (sodium sulfate) and concentrated and the crude product used without further purification MS (ER) t/2 282.19 (M-H1). -1H-indol-5-ol (5.35 g, 18.98 mmol) was dissolved in THF (90 ml) and cooled to 0 °C. TBAF (tetrabutylammonium fluoride) (4.96 g) was added to the brown solution over 5 min. , 18.98 mmol.) After 1 hour, the reaction is stopped with ammonium chloride.

The reaction mixture was diluted with ethyl acetate and washed with water and then brine.

The organic phase is separated, dried (sodium sulfate) and concentrated. The mixture is absorbed on silicon dioxide and purified by KFC (0-40 905 ethyl acetate:heptanes) to obtain the desired compound as a solid. MS (IER) t/2 168.15 (M--1). 116-E. Tert-butyl ether of 4-(4-chloro-1H-indol-5-yloxy)-5,7-dihydro-pyrrolo|3,4-4|pyrimidine-6-carboxylic acid. c) 5-4

M

They are

SI

It is obtained by a method similar to that described in example 44-B. MS (ER) t/2 388.96 (M-g2).

Example 117 117-А. 4-Methyl-1H-indole-5-ol.

M in on 5-Methoxy-4-methyl-1H-indole (10 g, 62.0 mmol) is dissolved in DCM (400 ml) and cooled to 0 "b. During 1 h. add VVgz (155 ml, 155 mmol) and the black mixture was allowed to warm to room temperature overnight (17 h). The reaction mixture was poured into a mixture of ice and sodium bicarbonate solution (aq) and extracted with ethyl acetate (1.5 L) and concentrated to give a black oil. The oil was absorbed on silicon dioxin and purified by KFC (0-50 95 ethyl acetate:heptanes) to obtain the desired compound in the form of a solid substance. MS (PER) it/2 148.23 (M--1). 117-8. tert-butyl 4-(4-methyl-1H-indol-5-yloxy)-5,7-dihydropyrrolo|3,4-4|pyrimidine-6-carboxylic acid ester. c) o-

M

N

M M h chu o is

It is obtained by a method similar to that described in example 448. MS (IER) t/2 367.01 (M.n1). 117-S. Tert-butyl ether (5)-6-methyl-4-(4-methyl-1H-indol-5-yloxy)-5,8-dihydro-6H-pyridoyl3,4-α|pyrimidine-7-carboxylic acid. n, M

N x shi (c) is

It is obtained by a method similar to that described in example 31-C. MS (ER) t/2 395.2 (M.n1).

Example 118 118-А. 4-chloro-5,6,7,9-tetrahydropyrimido|4,5-c|Iazepine-8-carboxylic acid tert-butyl ether and 118-8. Tert-butyl ether of 4-chloro-5,7,8,9-tetrahydro-1,3,6-triazabenzocycloheptene-b6-carboxylic acid.

She and KhD

M 2 Mo

OO S

M ro M var 118-8

A mixture of 1-tert-butyl ether, 4-ethyl ether of 3-oxoazepane-1,4-dicarboxylic acid and 1-tert-butyl ether, 3-ethyl ether of 4-oxoazepane-1,3-dicarboxylic acid is prepared as described in U. May. Spent 1986. -carboxylic acid and tert-butyl ether of 4-oxo-3,4,5,6,7,9-hexahydropyrimido|4,5-c|azepine-3-carboxylic acid, which is then converted into the desired compounds by a method similar to the one described in example 47E, and then separated into isomers 118-A and 118-8 using KFC (15-45 95 EIOAc/heptane. MS (IER) t/2 284.0 (M--1) for both isomers.

The following compounds are obtained by a similar method. 118-S. Tert-butyl ether of 4-chloro-5,6,8,9-tetrahydropyrimido|4,5-4|azepine-7-carboxylic acid.

SI

(6)

M zh

And H

MS (ER) t/2 284.0 (M--1).

Example 119

The following compounds are obtained by a method similar to that described in example 47-03. 119-A. Tert-butyl ether of 4-(1H-indol-5-yloxy)-5,6,7,9-tetrahydro-pyrido|2,3-c|azepine-8-carboxylic acid.

N

M uv, (c) so chu oz" M

WITH;

MS (ER) t/2 381.1 (M-n1) 119-8. Tert-butyl ether of 4-(1H-indol-5-yloxy)-5,7,8,9-tetrahydro-1,3,6-triazabenzocycloheptene-b-carboxylic acid.

N uv, / ; more;

M

-

M

MS (ER) t/2 381.1 (M-n1) 119-С. Tert-butyl ether of 4-(1H-indol-5-yloxy)-5,6,8,9-tetrahydro-pyrimido|4,5-4|azepine-7-carboxylic acid.

N

M u; (c) c)

M

Hmm | A x I

MS (ER) t/2 381.0 (M-n1)

Example 120 120-А. 5,7-Dihydro-ZN-thienoyi3,4-4|pyrimidin-4-one. at

Um what

IN

M

Commercially available 4-carbmethoxytetrahydro-3-thiophenone (5 g, 31.2 mmol) was dissolved in EN (284 mL). Then formamidine acetate (22 g, 211 mmol) was added, followed by sodium ethoxide (45 mL, 121 mmol, 21 95 w/w) and the mixture was heated at 90 °C for 14 h. The reaction mixture was cooled to room temperature and concentrated to give the residue, which is absorbed on silica and purified by KFC (0-10 95 methanol:SNeSig), and the desired compound is obtained as a solid. MS (ER) t/2 155.14 (M-41). 120-8 4-(1H-Indol-5-yloxy)-5,7-dihydrothieno|3,4-4|pyrimidine. more) av;

MO M

N

WITH

It is obtained by a method similar to that described in example 31-C. MS (ER) t/2 270.07 (M-n1). 120-6. (2-Fluoro-3-trifluoromethylphenyl)-amide 5-(5,7-dihydrothieno|3,4-4|pyrimidin-4-yloxy)-indol-1-

carboxylic acid. (c) va; ! And in Ko x

M. E. We are

It is obtained by a method similar to that described in example 45-A. MS (IER) t/2 475.4 (Ma1). "NN

NMR (400 MHz, DMSO-av) 6 ppm 10.27 (5, 1 N), 8.56 (5, 1 N), 8.25 (a, U-9.09 Hz, 1 N) , 8.09 (a, U-3.79

Hz, 1 N), 7.91 - 7.95 (t, 1 N), 7.68 - 7.72 (t, 1 N), 7.47 - 7.51 (t, 2 N), 7, 17 (a, U-9.09 Hz, 1 N), 6.82 (j, 9-3.79 Hz, 1 N), 4.33 (a, 9-1.77 Hz, 4 N).

The following compounds are obtained by a similar method. 120-0. (5-(1-Trifluoromethylcyclopropyl)-isoxazol-3-yl|-amide of 5-(5,7-dihydrothieno|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

IS

(6) If grove; EE

M. 2 in no

M

From N

MS (IER) t/2 488.9 (M--1). "H NMR (400 MHz, DMSO-abv) 6 ppm 11.44 (5.1 H), 8.56 (5.1 H), 8.30 (a, U-9.09 Hz, 1 H), 8.16 (y, 9-3.79 Hz, 1 H), 7.49 (a, 9-2.53 Hz, 1 H), 7.18 (a, 2U-8.84 Hz, 1 N), 7.04 (5.1 N), 6.78 (9, U-3.79 Hz, 1 N), 4.33 (a, U-1.77 Hz, 4 N), 1, 57 (a, 9U-1.52 Hz, 2 H), 1.57 (a, 9U-9.60 Hz, 2 H). 120-E. 15-(1-Methylcyclopropyl)-1H-pyrazole-3 -yl|-amide of 5-(5,7-dihydrothieno|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid. (c)

There is U

! I am MN

M. 2 to the garden

M

With o n

MS (IER) t/2 433.0 (M--1). "H NMR (400 MHz, DMSO-av) b frequency/million 8.55 (5, 1 H), 8.30 (a, 9-9.09 Hz, 1 H), 8.17 (9, 9 -3.79 Hz, 1 N), 7.46 (a, 9-2.78 Hz, 1 N), 7.13 (a, 9-9.09 Hz, 1 N), 6.72 (a, 9U-3.79 Hz, 1 H), 6.28 (5, 1 H), 4.33 (y, 9-2.02 Hz, 4 H), 1.41 (5, C H), 0, 93 (a, 9U-2.02 Hz, 2 H), 0.78 (y, 9-2.02 Hz, 2 H). 120-E. (5-Isopropylisoxazol-3-yl)-amide 5-( 5,7-dihydrothieno|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid. (6) -ССо 7о

Mo U di

M

With o n

MS (IER) t/2 422.12 (M--1). "H NMR (400 MHz, DMSO-av) b frequency/million 11.27 (5.1 N), 8.56 (5.1 N), 8.30 (a, U-8.84 Hz, 1 H), 8.17 (a, 9-3.79 Hz, 1 H), 7.49 (a, 9-2.53 Hz, 1 H), 7.17 (da, 9-8.97, 2 ,40 Hz, 1 N), 6.77 (a, 9-3.79 Hz, 1 N), 6.70 (5, 1 N), 4.33 (j, 9-1.77 Hz, 4 N ), 3.11 (quintet, Y-6.82 Hz, 1 H), 1.29 (a, Y3-6.82 Hz, 6 H). 120-25. (5-Cyclopropylisoxazole-3-ylyl-amide 5-(5,7-dihydrothieno|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid. pf; ! hundred

M. 22 in nak

M

With o n

MS (ER) t/2 420.11 (M--1). "H NMR (400 MHz, DMSOO-av) 5 ppm 11.23 (5.1 H), 8.56 (5.1 H), 8.29 (a, U-8.84 Hz, 1 H), 8.16 (a, 9-3.79 Hz, 1 H), 7.48 (a, 9-2.27 Hz, 1 H), 7.17 (da, 9-8.97, 2 ,40 Hz, 1 N), 6.77 (a, 9-3.54 Hz, 1 N), 6.65 (5, 1 N), 4.33 (a, 9U-1.52 Hz, 4 N ), 2.14-2.21 (t, 1 N), 1.06-1.11 (t, 2 N), 0.92-0.97 (t, 2 N).

120-N. 5-(5,7-dihydrothieno|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (5-tert-butylisoxazol-3-yl)-amide. (c) c)

M. 22 M -edi in Khm o nn

MS (ER) t/ 436.14 (M-1). "H NMR (400 MHz, DMSO-av) b freq./million 11.28 (5.1 H), 8.56 (5.1 H), 8.30 (a, U-8.84 Hz, 1 H), 8.17 (a, 2-3.79 Hz, 1 H), 7.49 (y, 2-2.53 Hz, 1 H), 7.17 (da, 9-8.97, 2 ,40 Hz, 1 N), 6.77 (a, 9-3.79 Hz, 1 N), 6.68 (5, 1 N), 4.33 (a, 9-1.52 Gu, 4 N ), 1.34 (5.9 N). 120-I. (3-Trifluoromethylphenyl)-amide of 5-(5,7-dihydrothieno-3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid. (6) wav; !E

SH U.

With him What?

MS (ER) t/2 457.09 (M--1). "H NMR (400 MHz, DMSO-av) b frequency/million 10.39 (in, 1 H), 8.56 (5, 1 H), 8.28 (a, 2-8.84 Hz, 1 H), 8.08 - 8.15 (t, 2 H), 7.98 (y, U-8.34 Hz, 1 H), 7.61 - 7.69 (t, 1 H), 7, 47 - 7.54 (t, 2 NU, 7.17 (aa, 9U-8.97, 2.40 Hz, 1 H), 6.81 (y, 9-3.54 Hz, 1 H), 4 ... |pyrimidin-4-yloxy)-indole-1-carboxylic acid. (c) av; in

With him

MS (ER) t/ 434.12 (М-А1). "H NMR (400 MHz, DMSO-av) b frequency/million 11.24 (5.1 H), 8.56 (5.1 H), 8.30 (y, 9-9.09 Hz, 1 H), 8.17 (a, 9U-3.79 Hz, 1 H), 7.48 (a, 9-2.27 Hz, 1 H), 7.17 (da, 9-8.97.2 .40 Hz, 1 N), 6.77 (0.9-3.54 Hz, 1 N), 6.67 (5.1 N), 4.33 (y, 9-1.26 Hz, 4 N ), 1.46 (5.3 NN), 1.13 -1.17 (t, 2 N), 0.91 - 0.96 (t, 2 N).

Example 121 121-A. 15-(1-Trifluoromethylcyclopropyl)-isoxazol-3-yl|-amide 5-(6,6-dioxo-b,7-dihydro-5H-6-lambda"6"-thieno13,4-4|pyrimidine-4- yloxy)-indole-1-carboxylic acid.

IS

(6)

SSO Av c)

M. 22 in --di oon (6)

At 0 "C, prepare a stock solution of ammonium tetrahydratomolybdate (240 mg, 0.19 mmol) in 50 95 wt/vol aqueous peroxide solution (0.6 ml) and add 0.13 ml of the stock solution at 0 "C to a solution of 15 5-(5,7-dihydrothieno|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid -(1-trifluoromethylcyclopropyl)-isoxazol-3-yl|-amide (55 mg, 0.113 mmol) in EN (8 ml). After stirring overnight, the reaction was quenched with water and extracted with E(OAc). The desired compound was purified by HPLC eluting with a mixture of DHM:MeonH from 100:0 to 95:5. MS (IR) t/2 520.8 (M-- 1). "NN

NMR (400 MHz, DMSO-av) 6 ppm 11.45 (5, 1 N), 8.68 (5, 1 N), 8.31 (a, U-9.09 Hz, 1 N) , 8.17 (a, U-3.79

Hu, 1 H), 7.52 (a, 9-2.27 Hu, 1 H), 7.20 (ad, U-8.84, 2.53 Hz, 1 H), 7.04 (5, 1 N), 6.79 (a, 9-4.29 Hz, 1 N), 4.72 (9, 90-12.88 Gu, 4 N), 1.52 - 1.64 (t, 4 N ).

The following compounds are obtained by a similar method. 121-8. (2-Fluoro-3-trifluoromethylphenyl)-amide /5-(6,6-dioxo-b,7-dihydro-5H-b-lambda"b"-thieno|3,4- a|pyrimidin-4-yloxy) -indole-1-carboxylic acid.

(c) wav; ;

M. 2 U - M EE on o nn ER (c)

MS (ER) t/2 507.8 (M--1). 121-6b. 15-(1-Methylcyclopropyl)-1H-pyrazol-3-yl|-amide 5-(6,6-dioxo-6,7-dihydro-5H-b-lambda"6b"-thienoY3,4-4|pyrimidine- 4-yloxy)-indole-1-carboxylic acid. (in)

There is U

! MN

MO y -di - M po on (c)

MS (ER) t/2 465.9 (M--1).

Example 122

The following compounds are obtained by a method similar to that described in example 16-A. 122-A. 5-(6-Hydroxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid I(5-(1-Methylcyclopropyl)-isoxazol-3-yl|-amide. (6)

M. M schi already M no o nn

MS (ER) t/2 406.1 (M-n1) 122-8. (5-Cyclopropylisoxazol-3-yl)-amide of 5-(6-hydroxymethylpyrimidin-4-yloxy)-indole-1-carboxylic acid. (c) VSHF; ame

M. M what

M but o n

MS (ER) t/2 3921 (M-n1) 122-606. (5-Isopropyl-1H-pyrazol-3-yl)-amide 5-(b-hydroxymethylpyrimidin-4-yloxy)-indole-1-carboxylic acid. (6)

There is Z

! MN

M. 2 M 4. already M no o nn

MS (IER) t/2 393.1 (M-H1). "H NMR (400 MHz, DMSO-dv) 5 ppm 12.22 (bBg. 5., 1 H), 10.59 (5, 1 H), 8.65 (a, 9-1.01 Hz, 1 N), 8.32 (5, 1 N), 8.18 (Bg. 5., 1 N), 7.46 (a, 9-2.02 Hz, 1 N), 7.11 - 7.13 (t, 1 H), 6.98 (5, 1 H), 6.72 (y, 9-3.28 Gu, 1 H), 6.34 (5, 1 H), 5.58 -5.61 (t, 1 N), 4.51 (y, 9-5.81 Hz, 2 N), 2.97 (a, U-6.82

Hz, 1 NU, 1.25 (a, 2-7.07 Hz, 6 N). 122-0. 5-(6-Hydroxymethylpyrimidin-4-yloxy)-4-methylindole-1-carboxylic acid (5-Isopropyl-1H-pyrazol-3-yl)y-amide.

There is U

And I Mn

MO 2 M -1 already M but On

MS (IER) t/2 407.1 (Mt). "H NMR (400 MHz, DMSO-sdv) b freq./million 12.21 (5.1 N), 10.57 (5.1 N), 8.62 (a, 9-1.01 Hz, 1 H), 8.15-8.17 (t, 2 H), 7.05 (a, U-8.84 Hz, 1 H), 6.96 (5, 1 H), 6.83 (a, 9U-3.28 Gu, 1

H), 6.34 (5, 1 H), 4.50 - 4.53 (t, 2 H), 2.94 - 2.97 (t, 1 H), 2.24 (5, C H) , 1.25 (a, 9-6.82 Gu, 6 N). 122-E. 5-(b-Hydroxymethylpyrimidin-4-yloxy)-indole-1-carboxylic acid (5-Isopropylisoxazol-3-yl)y-amide. (in)

Ra;

M. 2 M NI

But he

MS (IER) t/2 394.05 (M-1). "H NMR (400 MHz, DMSOO-av) 6 ppm 11.28 (5.1 H), 8.65 (a, 9U-1.01

Hz, 1 H), 8.32 (a, 9U-8.84 Hz, 1 H), 8.18 (y, U-3.54 Hz, 1 H), 7.49 (a, 9-2, 27 Hz, 1 N), 7.16 (yes, U-8.97, 2.40

Hz, 1 N), 6.99 (a, 9-1.01 Gu, 1 N), 6.78 (a, 9-3.79 Hz, 1 N), 6.70 (5, 1 N), 5.61 (I, 9-5.81 Hz, 1 N), 4.52 (y, y-5.81 Hz, 2 N), 3.08 - 3.15 (t, 1 N), 1, 29 (a, U-6.82 Hz, 6 N). 122-R. I5-(1-Trifluoromethylcyclopropyl)-isoxazol-3-yl|I-amide of 5-(b-hydroxymethylpyrimidin-4-yloxy)-indole-1-carboxylic acid. ее и; SE! co

M. 2 M WE already M but On

MS (ER) t/2 460.12 (M'-1). "H NMR (400 MHz, DMSO-dv) 5 ppm 11.45 (5.1 H), 8.65 (a, U-1.01

Hz, 1 N), 8.32 (a, 9U-9.09 Hz, 1 N), 8.18 (a, U-3.79 Hz, 1 N), 7.49 (a, 9-2, 27 Hz, 1 N), 7.17 (yes, U-8.97, 2.40

Hz, 1 N), 7.04 (5, 1 N), 6.99 (a, 9U-1.01 Hz, 1 N), 6.79 (a, U-3.79 Hz, 1 N), 5.59 - 5.63 (t, 1 H), 4.51 - 4.54 (t, 2 H), 1.54 - 1.60 (t, 4 H).

Example 123

The following compounds are obtained by a method similar to that described in example 27-A. 123-A. 15-(1-Methylcyclopropyl)-isoxazole-3-yl|-amide 5-(6b-tetrazol-1-ylmethylpyrimidin-4-yloxy)-indole-1-carboxylic acid. (c) higher education institutions; ! co

M. 2 M schi

We "MM o nn

M, -

M

MS (ER) t/2 458.0 (M--1). 123-8. |5-(1-Methylcyclopropyl)-isoxazol-3-yl1-amide 5-(b-tetrazol-2-ylmethylpyrimidin-4-yloxy)-indole-1-carboxylic acid. (c) VSHF; co

M. M. M.; ch and "MM about nn

M |! haha

MS (ER) t/2 458.9 (M--n1) 123-6b. 5-(b-Tetrazol-2-ylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (5-Cyclopropylisoxazol-3-yl)y-amide.

M (c);

CO

(in)

M. 2 M and. re "MM o nn

M |! haha

MS (ER) t/ 444.01 (M-1). "H NMR (400 MHz, DMSO-av) b freq./million 11.24 (5.1 N), 9.04 (5.1 N), 8.67 (5.1 N), 8.30 ( a, U-8.84 Hz, 1 H), 8.17 (a, 9-3.79 Hz, 1 H), 7.50 (j, 9-2.53 Hz, 1 H), 7.17 (yes, 2-8.97, 2.40 Hz, 1 N), 7.10 (5, 1 N), 6.77 (a, 9U-3.79 Hz, 1 N), 6.65 (5 , 1 H), 6.13 (5.2 H), 2.14-2.21 (t, 1 H), 1.06 - 1.11 (t, 2H), 0.93 -0.97 ( t, 2 H). 123-0. (5-Isopropylisoxazol-3-yl)-amide of 5-(6-tetrazol-2-ylmethylpyrimidin-4-yloxy)-indole-1-carboxylic acid.

M., O

SG a c)

M. 2 M WE gli v o nn

EM

MS (ER) t/ 446.99 (M--1). "H NMR (400 MHz, DMSO-av) b freq./million 11.29 (5.1 N), 9.04 (5.1 N), 8.67 (0.9U-1.01 Hz, 1 H), 8.31 (a, U-9.09 Hz, 1 H), 8.18 (a, U-3.79 Hz, 1 H), 7.51 (a, 9-2.27 Hz, 1 H), 7.18 (a9, 9U-8.97, 2.40 Hz, 1 H), 7.11 (5, 1 H), 6.78 (y, 9U-3.79 Gu, 1 H ), 6.69 (a, 9U-1.01 Hz, 1 N), 6.13 (5.2 N), 3.11 (, 9-6.95 Hz, 1 N), 1.29 (and , 6 H). 123-E. (5-Isopropylisoxazol-3-yl)-amide of 5-(6-tetrazol-1-ylmethylpyrimidin-4-yloxy)-indole-1-carboxylic acid.

Ge) sut a c)

M. 2 M 4.

M

"MM o nn

M, -

M

MS (ER) t/2 446.98 (M--1). "H NMR (400 MHz, DMSO-av) b frequency/million 11.29 (5.1 N), 9.52 (5.1 N), 8.68 (y, 9-1.01 Hz, 1 H), 8.31 (y, 9U-8.84 Hz, 1 H), 8.18 (a, 9U-3.79 Hz, 1 H), 7.50 (a, 9-2.53 Hz, 1 H), 7.13 - 7.19 (t, 2 H), 6.78 (y, 9U-3.79 Hz, 1 H), 6.69 (5, 1 H), 5.89 (5 , 2 H), 3.11 (1.9U-6.57 Hz, 1 H), 1.29 (a, 9-6.82

Hz, 6 N). 123-R. 5-(b-tetrazol-1-ylmethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (5-Cyclopropylisoxazol-3-yl)y-amide.

M., 0 days a c)

M. 2 M NI already M tm o nn me

MS (ER) t/ 444.99 (M-1). "H NMR (400 MHz, DMSO-av) b frequency/million 11.24 (5, 1 H), 9.52 (z, 1 H), 8.68 (y, 9-1.01 Hz, 1 H), 8.31 (y, 9-9.09 Hz, 1 H), 8.17 (a, 9U-3.54 Hz, 1 H), 7.49 (a, 9-2.27 Hz, 1 N), 7.13 - 7.18 (t, 2 N), 6.77 (0.9-3.79 Hz, 1 N), 6.65 (5, 1 N), 5.88 (5 ,2 H), 2.14-2.21 (t, 1 H), 1.09 (aa, U-8,59, 2.53 Hz, 2 H), 0.95 (da, U-4, 93, 2.40 Hz, 2 N).

Example 124 124-A. 1-Methyl-3-(1-methylcyclopropyl)-1H-pyrazol-5-ylamine.

Ku m,

M.M

H

A solution of 3-(1-methylcyclopropyl)-3-oxopropionitrile (1.0 g, 8.1 mmol), methylhydrazine (0.56 g, 12.2 mmol) and Men (40 mL) was heated at 80 °C for 16 h Then the solution is concentrated in vacuum and the residue is suspended in 5 ml of DCM and 20 ml of heptane, filtered and the product is obtained. MS (IR) t/2 152.3 (M--1). 124-V. Phenyl ether (2-methyl -5-(1-methylcyclopropyl)-2H-pyrazol-3-yl|-carbamic acid.

N ku

M-M )-79 Fr.

It is obtained by a method similar to that described in example 5-0. MS (PER) t/2 272.2 (M-n1).

Example 125 1-methyl-5-(1-methylcyclopropyl)-1H-pyrazol-3-ylamine. and steering wheel, deceased

To a solution of 3-(1-methylcyclopropyl)-3-oxopropionitrile (1.0 g, 8.1 mmol) in EN (10 ml) add 4 n. NSI in dioxane (10 ml). The mixture is stirred at room temperature for 16 h.

Concentrate under reduced pressure, dissolve the residue in MeOH (40 mL) and treat with methylhydrazine (0.56 g, 12.2 mmol). The mixture is heated at 80 "С for 16 h. Then the solution is concentrated in vacuo and the residue is purified by HPLC to obtain the product. MS (IER) t/2 152.3 (M--1).

Example 126

Phenyl ether of (1-methyl-5-(1-methylcyclopropyl)-1H-pyrazol-3-yl|-carbamic acid.

N ko gu ra 79

Gu

It is obtained from the compound of example 125 by a method similar to that described in example 5-0. MS (IER) t/2 272.2 (М-А1).

Example 127 127-А. 3-(2,5-Dimethylpyrrol-1-yl)-1-methyl-1H-pyrazole. db stump r

ASON (1.5 ml) was added to a solution of 1-methyl-1H-pyrazol-3-amine (9.5 g, 98 mmol) and acetonylacetone (11.2 g, 98 mmol) in toluene (150 ml), boiling refluxed together with a device for separating water until the formation of water stops. Concentrate to dryness. The residue is purified using a flash column and the product is obtained. MS (ER) t/2 176.3 (M.n1). 127-V. Dimethylamide of 5-(2,5-dimethylpyrrol-1-yl)-2-methyl-2H-pyrazole-3-carboxylic acid. (6) - Shen a g to ut

To a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-methyl-1H-pyrazole (2.0 g, 11.4 mmol) in THF (100 ml) at -78 "C, add 2.5 M pVIII in hexane (5.5 mL, 13.7 mmol).After stirring for 1.5 h.

add dimethylcarbamyl chloride (1.26 mL, 13.7 mmol). In 10 minutes. the ice bath is removed and the reaction mixture is allowed to warm to room temperature and stirred at room temperature for 2 h. and then poured into water, the organic layer was separated and the aqueous layer was extracted with DCM. The organic layers are combined and concentrated. The residue is purified by KFC and the desired compound is obtained. MS (ER) t/2 247.2 (M.H1). 127-S. Dimethylamide of 5-amino-2-methyl-2H-pyrazole-3-carboxylic acid. (6)

Mem

A solution of potassium hydroxide (1.1 g, 19.5 mmol) in water (30 mL) and ethanol (30 mL) was added to a suspension of hydroxylamine hydrochloride (2.7 g, 39 mmol) in ethanol (50 mL). Add 5-(2,5-dimethylpyrrol-1-yl)-2-methyl-2H-pyrazole-3-carboxylic acid dimethylamide (1.6 g, 6.5 mmol) and reflux the mixture for 48 h . The contents of the flask are then concentrated under reduced pressure and the residue is suspended in DCM. The suspension is refluxed and then cooled to room temperature, filtered and the filtrate concentrated to give the crude product.

MS (ER) t/2 169.3 (M--1). 127-O. Phenyl ether of (5-dimethylcarbamoyl-1-methyl-1H-pyrazol-3-yl)-carbamic acid. (6) ra 79 (6) 4 )

It is obtained by a method similar to that described in example 5-0. MS (ER) t/2 289.1 (M-n1). 127-E. Phenyl ether (1-tert-butyl-5-methyl-1H-pyrazol-3-yl-carbamic acid

N va:

MAM )-9 shka,

It is obtained by a method similar to that described in examples 127-A-127-O, using 1-tert-butyl-1H-pyrazole-3-ylamine as a starting material. At the alkylation stage, iodomethane is used instead of dimethylcarbamyl chloride. MS (ER) t/ 274.3 (M--1).

Example 128 128-А. 3-(2,5-Dimethylpyrrol-1-yl)-5-isopropyl-1H-pyrazole

N. M

It is obtained by a method similar to that described in example 127-A using 5-isopropyl-1H-pyrazol-3-ylamine as a starting material. MS (ER) t/2 204.3 (M.H1). 128-8. 3-(2,5-Dimethylpyrrol-1-yl)-5-isopropyl-1-methyl-1H-pyrazole

To a solution of 3-(2,5-dimethylpyrrol-1-yl)-5-isopropyl-1H-pyrazole (7.7 g, 37.9 mmol) in THF (400 ml), purged with nitrogen, at 0 "C is added Mann (2.272 g, 56.8 mmol). The mixture was stirred for 10 min in an ice bath, then for 10 min at room temperature. Mei (4.74 mL, 76 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture is then diluted with DCM and treated with saturated ammonium chloride solution (10 mL). The mixture is concentrated to dryness and the residue is partitioned between water and DCM. The combined organic layer is dried over sodium sulfate, concentrated and absorbed over silica and purified with the help of KFC (0-30 96 ESUAS)/heptane) and obtain 5-(2,5-dimethylpyrrol-1-yl)-3-isopropyl-1-methyl-1H-pyrazole (2.4 g,

239 9o) corresponding to the first peak and 3-(2,5-dimethylpyrrol-1-yl)-5-isopropyl-1-methyl-1H-pyrazole (5.24 g, 63 95) corresponding to the second peak . MS (IER) t/2 218.3 (t-1). 128-606. 5-Isopropyl-1-methyl-1H-pyrazole-3-ylamine

And gum p

It is obtained by a method similar to that described in example 127-C, using 3-(2,5-dimethylpyrrol-1-yl)-5-isopropyl-1-methyl-1H-pyrazole as a starting material. MS (ER) t/2 140.3 (M--1). 128-0. Phenyl ether (5-isopropyl-1-methyl-1H-pyrazol-3-yl)-carbamic acid

N

A gud r 9 sha

It is obtained by a method similar to that described in example 5-O, using 5-isopropyl-1-methyl-1H-pyrazol-3-ylamine as a starting material. MS (IER) t/2 260.2 (M-n1).

The following compounds are obtained by a similar method.

SHY Structure/chemical name MS (ER) t/2 (M-1 (F) in U o 128-E - that 286.2 phenyl ether (5-cyclopropyl-1-isopropyl-1H-pyrazol-3-yl) - carbamic acid

IS

Oh)

AC

-U-M 128-E MAN 326.2 g phenyl ether (1-methyl-5-(1-trifluoromethylcyclopropyl)-1H-pyrazol-3-yl|-carbamic acid

Example 129 129-А. 5-Cyclopropyl-3-(2,5-dimethylpyrrol-1-yl)-1H-pyrazole

N. M

It is obtained by a method similar to that described in example 127-A, using 5-cyclopropyl-1H-pyrazol-3-ylamine as a starting material. MS (ER) t/2 202.4 (M-n1). 129-8. 1,5-Dicyclopropyl-3-(2,5-dimethylpyrrol-1-yl)-1H-pyrazole

A suspension of copper(I) acetate (0.902 g, 4.97 mmol) and 2,2'-bipyridine (0.776 g, 4.97 mmol) in DHE (20 ml) is stirred at 70 "C for 15 min., then transferred into a suspension of potassium cyclopropyl trifluoroborate (1.47 g, 9.94 mmol) and 5-cyclopropyl-3-(2,5-dimethylpyrrol-1-yl)-1H-pyrazole (1 g, 4.97 mmol) and sodium carbonate (1.053 g, 9.94 mmol) in DHE (40 mL).

the green mixture is stirred at 70 "C for 24 hours. The reaction mixture is subjected to distribution between

EYUASs and 1 n. NOSE The aqueous layer is extracted with EOAc. The combined organic layers were washed with brine, dried (Mag25O4) and concentrated. The residue (1.64 g) is purified with the help of ISO (EIAs-heptane 0-30 95) and the desired product (1.25 g) is obtained in the form of a colorless oil. MS (IER) t/2 242.3 (M--1). 129-6. 1,5-Dicyclopropyl-1H-pyrazole-3-ylamine lu, a

It is obtained by a method similar to that described in example 127-C, using 1,5-dicyclopropyl-3-(2,5-dimethylpyrrol-1-yl)-1H-pyrazole as a starting material. MS (ER) t/2 164.4 (M.n1). 129-Yu. Phenyl ether (1,5-dicyclopropyl-1H-pyrazol-3-yl-carbamic acid bu

MAM )-T9 cho

It is obtained by a method similar to that described in example 5-O, using 1,5-dicyclopropyl-1H-pyrazol-3-ylamine as a starting material. MS (ER) t/2 284.2 (M.n1).

Example 130 130-А. 2-(5-(2,5-Dimethylpyrrol-1-yl)-2-methyl-2H-pyrazol-3-yl|-1,1,1-trifluoropropan-2-ol.

And he

Eh - Eh

Ukeukh dr

E AM-M

To a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-methyl-1H-pyrazole (1.5 g, 8.6 mmol) in THF (100 ml) at -78 °C, add 2.5 M pVIII in hexane (4.1 mL, 10.3 mmol) and stirred for 1.5 h, then ethyl trifluoroacetic acid (1.5 g, 10.3 mmol) was added. After 10 min, the ice bath was removed and the reaction mixture is allowed to warm to room temperature. Then the reaction mixture is cooled again to -78 "C and methylmagnesium bromide (1.0 M solution in hexane, 8.6 ml) is added.

In 5 minutes. the ice bath is removed and the mixture is stirred at room temperature for 3 h, poured into water, the organic layer is separated and the aqueous layer is extracted with DCM.

The organic layers are combined and concentrated. The residue is purified by KFC and the desired compound is obtained. MS (IER) t/2 288.1 (M--1). 130-8. 3-(2,5-Dimethylpyrrol-1-yl)-1-methyl-5-(2,2,2-trifluoro-1-methoxy-1-methylethyl)-1H-pyrazole. -Zhho (6)

IS

And t6eitvya uUteu same

To a solution of 2-(5-(2,5-dimethylpyrrol-1-yl)-2-methyl-2H-pyrazol-3-yl|-1,1,1-trifluoropropan-2-ol (0.5 g, 1 .7 mmol) in THF (10 ml) at 0 "С add sodium hydride (0.21 g, 6095, 5.2 mmol) and the mixture is stirred for 10 min., then add methyl iodide (0.22 ml, 3.5 (mmol). The ice bath is removed, and the reaction mixture is stirred at room temperature for 5 h, poured into water, the organic layer is separated, and the aqueous layer is extracted with DCM. The organic layers are combined and concentrated. The residue is purified by KFC to give the desired compound. MS (ER) t/2 302.0 (M--1). 130-60. 1-Methyl-5-(2,2,2-trifluoro-1-methoxy-1-methylethyl)-1H-pyrazole -Z3-ilamine.

o7

Oh, and

A solution of potassium hydroxide (280 mg, 5 mmol) in water (b mL) and ethanol (b mL) was added to a suspension of hydroxylamine hydrochloride (700 mg, 10 mmol) in ethanol (9 mL). Then add 3-(2,5-dimethylpyrrol-1-yl)-1-methyl-5-(2,2,2-trifluoro-1-methoxy-1-methylethyl)-1H-pyrazole (500 mg, 1.7 mmol) and the mixture is refluxed for 24 hours. The contents of the flask are then concentrated under reduced pressure and the residue partitioned between water and DCM and separated. The aqueous layer is extracted with DCM and the organic layers are combined and concentrated to give the crude title compound. MS (IER) t/2 224.2 (M-n1). 130-О0О. Phenyl ether /(P-methyl-5-(2,2,2-trifluoro-1-methoxy-1-methylethyl)-1H-pyrazol-3-yl|- carbamic acid. -ХУ (c) (c) у у - in-9

M poly Z ra

It is obtained by a method similar to that described in example 5-0. MS (ER) t/2 344.0 (M-n1).

Example 131 131-А. 3-(5-Amino-2H-pyrazol-3-yl)-3-methylbutan-1-ol.

M on

It is obtained by a method similar to that described above in example 5-B, using a,a-dimethyl-y-butyrolactone as a starting material. MS (ER) t/ 170.1 (M--1). 131-8. 4,4-Dimethyl-5,6-dihydro-4H-pyrrolo|1,2-b|pyrazol-2-ylamine. pelvis

Thionyl chloride (7.22 ml, 99 mmol) was added to a solution of pyrazole obtained above (3.35 g, 19.F8 mmol) in THF (100 ml) at RT. Stirring is continued for 2 hours, then the mixture is slowly added to 200 ml of 2895 MNAON and 100 g of ice. Then the aqueous suspension is extracted with DCM (2x200 ml) and the combined organic layers are dried (Mag250O054), filtered and concentrated.

Then the residue is purified by KFC (1-10 96 Meon/DHM) and the desired compound is obtained. MS (ER) t/2 1521 (M-n1). 131-S. Phenyl ether of (4,4-dimethyl-5,b-dihydro-4H-pyrrolo|1,2-5|pyrazol-2-yl)y-carbamic acid.

N. M

ORI

Lutidine (3.30 ml, 28.4 mmol) was added to a solution of the compound of example 131-8 (1.43 g, 9.46 mmol) and DCM (50 ml) at 0 "С, then phenyl chloroformate (1.31 ml, 10.4 mmol). The solution is stirred at RT for 4 h. Then the solution is washed with 2 M HCl and then the organic layer is dried (Mag2504), filtered and concentrated. Then the residue is purified using KFC (300-100 95

EtOAc/heptane) and obtain the desired compound. MS (IER) t/2 272.1 (M--1).

The following compounds are obtained by a similar method. 131-O. Phenyl ether of (3Z-chloro-4,4-dimethyl-5,6-dihydro-4H-pyrrolo|1,2-5|pyrazol-2-yl)-carbamic acid.

N M o 5 Hom

ORI SI

It is obtained from 3-chloro-4,4-dimethyl-5,6-dihydro-4H-pyrrolo|1,2-B|pyrazol-2-ylamine, which is isolated as a by-product during the above preparation of the compound of example 131-8. MS (IR) t/2 306.0, 308.0 (M-y1). 131-E. Phenyl ether of (5,6-dihydro-4H-pyrrolo|1,2-5|pyrazol-2-yl)-carbamic acid.

N. M

DZ

ORI

MS (ER) t/2 244,086.1 (M.H1). 131-R. Phenyl ether of (4,4-dimethyl-4,5,6,7-tetrahydropyrazolo|1,5-a|Ipyridin-2-yl)y-carbamic acid.

N M o and ah

ORI

MS (ER) t/2 286.1 (M--1).

Example 132 132-А. (4-chloro-5-cyclopropylisoxazol-3-yl)y-carbamic acid phenyl ether

In /

SI MN o- o

Phenyl ether of 5-cyclopropylisoxazole-3-yl-carbamic acid (0.25 g, 1.024 mmol) is dissolved in ASON (7.31 ml) and MO5 (0.205 g, 1.53 mmol) is added and the reaction mixture is heated at 79 "С for 2 h.The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate.The organic layer was washed with 500 mL of water to remove the acid.

The organic layer was dried (sodium sulfate) and concentrated to give the desired compound as an oil (352 mg), which was used without further purification. MS (ER) t/2 279.00 (M--1).

The following compounds are obtained by a similar method. 132-8. Phenyl ether of (5-tert-butyl-4-chloroisoxazol-3-yl)-carbamic acid.

IF) i

SI MN o-K

IF)

MS (ER) t/2 295.02 (M-n1). 132-S. Phenyl ether of (4-chloro-5-(1-methylcyclopropyl)-isoxazole-3-yl]-carbamic acid.

so what

SI MN o- (6)

MS (ER) t/2 293.01 (M-n1).

Example 133 133-А. Phenyl ether (5-cyclopropyl-4-methylisoxazol-3-yl)-carbamic acid (c) di

MN

0-0 (c)

(5-Cyclopropylisoxazol-3-yl)y-carbamic acid phenyl ether (0.368 g, 1.51 mmol) was dissolved in THF (10 mL) and cooled to -78 °C and purged with nitrogen. Then n-butyllithium (2, (17 mL, 3.47 mmol). The mixture was stirred in a solid carbon dioxide/acetone bath for 30 min. Undiluted methyl iodide (0.10 mL, 1.66 mmol) was added and the reaction mixture was stirred for 2 h at -78 °C. The reaction is stopped (0 "C) with 20 ml of saturated ammonium chloride solution, diluted with ethyl acetate and the organic layer is separated, dried (sodium sulfate) and concentrated to give an oil, which is purified by KFC (0-40 95 ethyl acetate:heptanes) to give the desired compound in the form of oil MS (ER) t/2 259.20 (M.n1).

The following compounds are obtained by a similar method. 133-V. Phenyl ether of (5-tert-butyl-4-methylisoxazol-3-yl)-carbamic acid. ) poison

MN o-K c)

MS (ER) t/2 275.24 (Mt) 133-S. Phenyl ether of (4-methyl-5-(1-methylcyclopropyl)-isoxazole-3-yl]-carbamic acid.

IF) what

MN o-0

IF)

MS (ER) t/2 273.17 (M-1). 133-O. Phenyl ether of (5-tert-butyl-4-methoxymethylisoxazol-3-yl)-carbamic acid.

(c) di

Me MN o-K (c)

MS (IER) t/: 305.00 (M'1).

Example 134

The compounds indicated below are obtained by methods similar to those described in examples 54 and 56. p. MS (IER) 1

WHAT Structure/chemical name NMR (400 MHz)

Mo with CE (DMSO-dv) b freq./million 8.36 (5, and dl and 1 N), 8.30 (a, 2-91 Hz, 1 N),

M. 2 M no iv) 8.14 (a, 9-38 Hz, 1 H), 7.40 (a, p M y-2.5 Hz, 1 H), 7.08 (aa, 9U-9 ,0, 134-A M o nn 2.4 Hz, 1 N), 7.04 (5, 1 N), 6.74 499.1

H (a, 9-3.5 Hz, 1 H), 3.96 (5.2 H), (5-(1-trifluoromethyl-cyclopropyl)- 300 732 (t, 4 H), 170 1.81 isoxazole -Z-yl|-amide 5-(6,7,8,9-tetrahydro- (t, 2 H), 1.49 -1.60 (t, 4 H)

BN-pyrimido|4,5-c|azepin-4-yloxy)-indole-1-carboxylic acid o (DMSO-dv) 6 ppm 8.35 (5, ha X 1 H), 8.30 ( a, 2-91 Hz, 1 H), so 8.13 (a, 9-38 Hz, 1 H), 7.38 (y,

M M zdi y-2.5 Hz, 1 H), 7.06 (aa, 9U-9.0, rya 271 Hz, 1 H), 6.70 (a, 9U-2.8 Hz, 1 134- 8 M o n H), 6.64 (5.1 H), 3.93 (5.2 H), 431.1

H 2.96 - 3.13 (t, 4 H), 2.09-2.22 (5-cyclopropylisoxazol-3-yl)-amide 5- (t, 1 H), 1.68 - 1.82 ( t, 2 H), (6,7,8,9-tetrahydro-5H-pyrimido|4,5- 1,038-1,15(t,2 H), 0,88 - 0,97 s|azepin-4- yloxy)-indole-1-carboxylic (t,2 H) acid

M. ,0 (DMSO-dv) 6 parts/million 8.37 (5,

Ty Te ВХ and 1 N), 8.29 (a, 2-91 Hz, 1 N),

M. 2 M about 8.15 (a, 9U-3.5 Hz, 1 N), 7.40 (a,

M y-2.3 Hz, 1 H), 7.09 (aa, 9U-9.0, 134-С МН обы 2.A hz, 1 H), 6.74 (9.9-3.5 HZ, 1 | 447

H), 6.68 (5.1 H), 4.03 (5.2 H), (5-tert-butylisoxazol-3-yl)-amide 5- 3.02 - 3.13 (t, 4 H ), 1.63 - 1.75 (6,7,8,9-tetrahydro-5H-1,3,6- (t, 2 H), 1.34 (5, 9 H) triazabenzocyclohepten-4-yloxy) -indole-1-carboxylic acid o (DMSO-dv) 6 ppm 8.36 (5, ha X 1 N), 8.28 (a, 2-8.84 Hz, 1 N), so 8, 15 (a, 9U-3.79 Hz, 1 N), 7.40 (a,

Mo U. here y-2.53 Hz, 1 N), 7.09 (aa,

Y M 98.97, 2.40 Hz, 1 N), 6.74 (y,

T3Ko m on 4-3.54 Hz, 1 N), 6.68 (5, 1 N), m

H 3.94 (in, 2 H), 3.01 - 3.10 (t, 4 (B-tert-butylisoxazol-3-yl)-amide 5- H) 1.69 - 1.81 (t, 2 NU, 1,94 (5, (6,7,8,9-tetrahydro-5H-pyrimido|4,5- 9H)siazepin-4-yloxy)-indole-1-carbon

1 fkislotiiG///1111111111111G1 (se she; where (dme sv) b chastmln 8.32 - i i "38 (t, 2 H), 8.12 (i, 9-3.79

M. M more. Hz, 1 N), 7.37 (a, y-2.27 Hz, 1

OZ r M H), 7.06 (ad, U-8.84, 2.27 Hz, 1 134-E M o nn H), 7.03 (v, 1 H), 6.68 (j, 9 -3.54 499.0

H HC, 1 H), 3.06 (i, U-9.22 Hz, 4 H),

I5-(1-trifluoromethyl-cyclopropyl)- 2.89 - 2.98 (t, 4 H) 1.49 - 1.57 isoxazol-3-yl|-amide 5-(6,7,8,9-tetrahydro - (t, 4 N)

BN-pyrimido|4,5-d|azepin-4-yloxy)-indole-1-carboxylic acid "more (DMSO-dv) 6 ppm 10.62 (5, where x 1 H), 8, 37 (5.1 H), 8.28 (a,

M. m CM 9-8.84 Hz, 1 H), 8.14 (y, 9-3.79

U. zd Hz, 1 H), 7.37 (9.9-2.27 Hz, 1

IZ E MN o MN H), 7.06 (ad, 9-8.97, 2.40 Hz, 1 4722

Н Н), 6.69 (a, 9-3.28 Hz, 1 Н), 6.40 ; (4,4-dimethyl-4,5,6,7-tetrahydro- (5, 1 H), 4.02 (5, 2 H), 3.96 (Her, pyrazolo|1,5-a|pyridine- 2-yl)-amide 5-Y-6.19 Hz, 2 H), 3.02 - 3.11 (t, (6,7,8,9-tetrahydro-5H-1,3,6- 4 H ) 1.95-2.06 (t, 2 H), 1.64 - triazabenzocyclohepten-4-yloxy)-indole-| 1.74 (t, 4 N) 1.30 (5, 6 N) 1-carboxylic acid (DMSO-dv) 6 ppm 10.61 ke (Bk. 5., 1 N), 8.37 ( 5, 1 H), 8.27 pe X (a, 9-8.84 Hz, 1 H), 8.13 (4,

M. is M and M 923.79 Hz, 1 N), 7.38 (9.9-2.53

IR Hz, 1 N), 7.06 (da, U-8.84, 2.27 134-0 MN X-m Hz, 1 N), 6.70 (a, 9-3.28 Hz, 1 458 ,2 on H), 6.27 (in, 1 H), 4.09 (i, 2-6.95 (4,4-dimethyl-5,6-dihydro-4H-pyrrolo|1,2- | Hz , 2 H), 4.04 (5.22 H), 3.08 pIpyrazol-2-yl)-amide 5-(6,7,8,9-tetrahydro-| (ada, 9U-10.80, 5 .68, 5.49 Hz, 4

BN-1,3,6-triazabenzocycloheptene-4-H), 2.931 - 2.36 (t, 2 H), 1.67 - yloxy)-indole-1-carboxylic acid 1.77 (t, 2 H), 1.32 (5, 6 N) (DMSO-dv) 6 ppm 10.61 (5,

Mao 1 H), 8.35 (5, 1 H), 8.27 (4, and If; d 9-8.84 Hz, 1 H), 8.13 (y, 9-3.79

M. 22 M i M Hz, 1 H), 7.38 (y, U-2.53 Hz, 1 re M H), 7.06 (ad, 9U-8.97, 2.40 Hz, 1 134 -H o nn H), 6.70 (4.9-3.79 Hz, 1 H), 6.27, 458.2 yh (5, 1 NU, 4.09 (y, U-6.82 Hz . 9-6.95 Hz, 2 N), 1.70

Bipyrazol-2-yl)-amide 5-(6,7,8,9-tetrahydro- -1.79 (t, 2 H), 1.32 (v, 6 H)

BN-pyrimido|4,5-s|azepin-4-yloxy)-indole-' 'cho' 1-carboxylic acid (DMSO-dv) 6 ppm 8.36 (5,

MO x 1 H), 8.28 (4, 9-8.84 Hz, 1 MH), and 8.14 (a, 9-3.54 Hz, 1 H), 7.39 (4,

Mo M - 9-2.53 Hz, 1 H), 7.08 (give, p M 9-8.97, 2.40 Hz, 1 H), 6.71 (a, 134-I M o nH 923 .54 Hz, 1 N), 6.64 (5.1 N), 4311

H 3.04 (a, 9-10.04, 4.96 Hz, 4 H), (5-cyclopropylisoxazol-3-yl)-amide 5- 2.85- 2.93 (t, 4 H) 2, 16 (H, (6,7,8,9-tetrahydro-5H-pyrimido|4,5- 98.37, 5.02 Hz, 1 H), 1.03 -

Phiazepin-4-yloxy)-indole-1-carboxylic acid 1710 (t, 2 H), 0.89 - 0.96 (t, 2 H acid)

(DMSO-dv) 6 parts/million 10.63

Mo x (g. 8., 1 H), 8.55 (5, 1 H), 8.28

That's If; m (a, 9-91 Hz, 1 N), 8.15 (a, 9-3.5

My U. here Hz, 1 H), 7.45 (y, 9U-2.5 Hz, 1 H), 7.12 (ad, y-8,8,2.5 Hz, 1 H), 18345 and on 6.71 (a, 0e3.5 HZ, NN), 6.27(5, 0 (44-dimethyl-5,6-dihydro-4H-pyrrolo|1,2- ! Н) 4.05 - З (t, 6 Н ), 23 y y : y (imaginary y, U-6.9 Hz, 2 N), 1.32

B|pyrazol-2-yl)-amide 5-(6,7-dihydro-5|H- (in, 6 H) pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1- | 7" carboxylic acid (DMSO-dv) 6 ppm 10.62 (5,

M. ,0 1 N), 8.40 (5.1 N), 8.27 (y, 9-91

Tj t If; where Hz, 1 N), 8.14 (a, 9U-3.8 Hz, 1 N),

M. Z M /x 7.A1 (in, 1 N), 7.08 (yes, U-9.0, rya M 2.4 Hz, 1 N), 6.70 (y, 9-3.5 Hz, 1 134-K M» o and H), 6.27 (5, 1 H), 4.09 (imaginary i, 458.1

H uU-6.9 Hz, 2 H), 3.75 - 3.98 (t, 2 (44-dimethyl-5,6-dihydro-4H-pyrrolo|1,2- H), 2.89 - 3 .05 (t, 1 H), 2.85

Bipyrazol-2-yl)-amide 5-((5)-6-methyl- (aa, U-16,8, 3.4 Hz, 1 H), 2,24 - 5,6,7,8-tetrahydropyrido |3 4-a|pyrimidine- | 2270 (t, Z H), 1.92 (5, 6 NU, 1,21 4-yloxy)-indole-1-carboxylic acid (9, 9-63 Hu, Z H ) "more; (DMSO-dv) 6 parts per million 10.62 (5, i se x 1 N), 8.37 (5.1 N), 8.28 (a, o CM 9-9.09 Hz, 1 N), 8.15 (y, 9U-3.79

M Hz, 1 H), 7.38 (y, 9-2.27 Hz, 1

X-m H), 7.06 (yes, U-8.84, 2.27 Hz, 1 134-I M o n H), 6.69 (y, 92-3.54 Hz, 1 NN), 6,401... 4722

H (5, 1 H), 3.93 - 4.01 (t, 4 H) (44-dimethyl-4,5,6,7- 3.03 - 3.13 (t, 4 H) 1.98 - 2.06 tetrahydropyrazolo|(1,5-a|Ipyridin-2-yl)-|(t, 2 H), 1.73 -1.81 (t, 2 H), amide 5-(6,7, 8,9-tetrahydro-5H- 1,64 -1,70 (t, 2 H), 1,30 (5, 6 pyrimido|4,5-s|azepin-4-yloxy)-indole-1- | H ) carboxylic acid (DMSO-dv) 6 ppm 10.64 (5, o 1 N), 8.53 (c, 1 N), 8.31 (a, 5-8.8

Mach X Hz, 1 H), 8.17 (a, 9U-3.8 Hz, 1 H), (y ah 7.43 (9, 9-52.3 Hz, 1 H), 7.10 (aa ,

M. M s 99.0, 2.4 Hz, 1 N), 6.72 (y, . p 93.8 Hz, 1 N), 6.40 (5.1 N), 134-M MO o nn 4.18-4.A1(t.2 H), 3.p90-4.02 472.2

H (t, 2 H), 3.44 - 3.64 (t, 1 H), (44-dimethyl-4,5,6,7- 3,13 (aa, U-17,6,4,2 Hz, 1 H), tetrahydropyrazolo|1,5-a|pyridin-2-yl)- |2.66 (da, 9U-16.8, 10.7 Hz, 1 H), amide 5-((5) -6-methyl-5,6,7,8-tetrahydro-|1.94 - 2.08 (t, 2 H), 1.60 - 1.75 pyrido-3,4-a|pyrimidin-4-yloxy)- indole-1- | (t, 2 N), 1.39 (a, 9-66 Hz, C H), carboxylic acid 1.30 (5.6 N (DMSO-dv) 6 ppm 10.59 (5,

M i); 1 H), 8.40 (c, 1 H), 8.28 (a, 5-8.8

That is IF; dp Hz, 1 N), 8.15 (a, 9U-3.8 Hz, 1 N),

M. 2 M that M 7.A1 (a, 9-23 Hz, 1 H), 7.08 (yes,

Khm M U-8.8, 2.3 Hz, 1 N), 6.71 (4, zi, 93.5 Hz, 1 N), 6.28 (5.1 N), 13A-M and on 4 ... 2 H), 2.91 - 3.03 (t, 1 yl)-amide 5-((5)-6-methyl-5,6,7,8-Nu, 2.78 - 2.92 (t, Z H), 2.54 - tetrahydropyridoyi3,4-4|pyrimidine-4-2,b2 (t, 1 NU, 2,33 (90, U-16,7, yloxy)-indole-1-carboxylic acid Mich Hz , 1 NU, 1.21 (a, U-6.3 Gu,

"more (DMSO-dv) 6 parts/million 8.39 (5,

TY - M t SE 1 H), 8.32 (a, 2-9.09 Hz, 1 H),

M. Zh M (o; 8.14 (a, 9U-3.79 Hz, 1 H), 7.39 (a,

M y-2.53 Hz, 1 H), 7.08 (aa, 134-0 MN Hm 98.97, 2.40 Hz, 1 H), 7.03 (5, 1 499.0 o n NU, 6.73 (y, 9-3.54 Hz, 1 N), 4.07

I5-(1-trifluoromethyl-cyclopropyl)-(5,2 H), 3,10 (a, 2-17,75, 5,40 isoxazol-3-ylI-amide 5-(6,7,8,9- tetrahydro-| Hz, 4 N), 1.67 - 1.79 (t, 2 N),

BN-1,3,6-triazabenzocycloheptene-4-1,48 - 1,60 (t, 4 H)yloxy)-indole-1-carboxylic acid (DMSO-dv) 6 parts/million 10.10

M. ,0 SI (g. 5., 1 H), 8.39 (in, 1 H), 8.23

That is IF; d (a, 9-91 Hz, 1 N), 8.04 (a, 9-3.8

M. and M What M Hz, 1 N), 7.43 (y, 9-2.5 Hz, 1 N), re M 7.10 (ad, 9-9.0.24 Hz, 1 N), "n 6.77 (9, 9-38 Hz, 1 N), 4.18 (i, 13AR her on Ch-7y Hz, 2 N), 3.78 - 3.97 (t, 2/2" 194 ,0 (3-chloro-4,4-dimethyl-5,b-dihydro-4H-H), 2.90 - 3.04 (t, 1 H), 2.85 pyrrolo(1,2-B|pyrazole -2-yl)-amide 5-((5)-6- | (99, U-16.8, 3.9 Hz, 1 H), 2,35-methyl-5,6,7,8-tetrahydropyridoi3 ,4- 2.43 (t, 2 H), 225 - 2.35 (t, 1 a|pyrimidin-4-yloxy)-indole-1-carbon H), 1.39 (5, 6 H), 1 .21 (a, U-6.3 acid Hz, C H) (DMSO-dv) 6 ppm 8.37 (5, more) 1 nH), 8.27 (a, 2-88 Hz, 1 H), ie t IF; d 8.14 (a, 9-38 Hz, 1 H), 7.39 (j,

M. M |c) y-2.5 Hz, 1 N), 7.09 (aa, 9U-9.0,

M 2.4 Hz, 1 H), 6.73 (y, 9U-3.8 Hz, 1 134-0) М ой H), 6.65 (5, 1 H), 4.04 (5.2 H), 431.1 3.03 -3.14 (t,4 NN), 212-222 (5-cyclopropylisoxazol-3-yl)-amide 5-(t, 1 H), 1.67 -1.76 (t,2 H), (6,7,8,9-tetrahydro-5H-1,3,6-1,04-1,12(t,2 H), 0.91 - 0.97 triazabenzocycloheptene-4 -yloxy)-indole-| (t, 2 N) of 1-carboxylic acid o I o M (MeО0b) 5 parts/million 8.53 (5, 1

Ma X H), 8.34 (a, 2-9.09 Hz, 1 H), 7.90 (y Jasoshch-- (a, 9-3.79 Hz, 1 H), 7.42 (y,

M. M z-d y-2.53 Hz, 1 H), 7.12 (aa, 134-8 M re 39-8.84, 2.27 Hz, 1 H), 6.79 (5.1 447.0

H o nn H), 6.72 (y, 9-3.54 Hz, 1 H), 4.20 (B-dimethylcarbamoyl-1-methyl-1 H-(a, -8.08 Hz, 4 H) , 3.86 (5, C H), pyrazol-3-yl)-amide 5-(6,7-dihydro-5H- 3.19 (5, C H), 3.13 (5, C H) pyrrolo |3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (mer) b parts/million 8.37 (5, 1

H), 8.31 (a, 2-9.09 Hz, 1 H), 7.86 o (a, 9-3.54 Hz, 1 H), 7.38 (y, he X uU-2, 27 Hz, 1 N), 7.08 (aa,

I 5-8.97, 2.15 Hz, 1 N), 6.70 (a,

М M zdi 93.03 Hz, 1 N), 6.32 (y, 91.26 134-5 yarya Hz, 1 N), 4.00 (y, U-5.05 Hz, 2 458.0

MO 7 o nn H), 3.86 (z, Z H), 3.12 (da, '

H 93.35, 1.58, 1.39 Hz, 1 H), 3.00

P-methyl-5-(1-methylcyclo-propyl)-1 H- (aa, 9U-17.05, 2.02, 1.89 Hz, 1-pyrazol-3-yl|-amide 5-((5) -6-methyl-5,6,7,8- | H), 2.51 (5, 1 H), 1.38 (5, C H), tetrahydro-pyrido|3,4-a|pyrimidine-4 - 1.34 (a, 9-6.32 Hz, C H) 0.89 (bg. yloxy)-indole-1-carboxylic acid 85.2 H) 0.77 - 0.84 (t, 2 H )

(DMSO-dv) 6 parts per million 8.40 (5, o 1 N), 8.25 (a, 9-9.09 Hz, 1 N), he X 8.04 (a, 9-3, 54 Hz, 1 N), 7.44 (4,

M 9-2.27 Hz, 1 H), 7.10 (aa,

M U. I M y-8.97, 2.40 Hz, 1 H), 6.77 (a,

M 3-3.54 Hz, 1 N), 6.05 (5.1 N), 1zit M b 3.83 (5.2 N), 3.65 (5.3 N), 3.04.). .770

H (y, 9U-5.81 Hz, 2 H), 2.73 (y, (r-methyl-5-(1-methylcyclo-propyl)-2H-9-5.68 Hz, 2 H), 1 .38 (5.3 H), pyrazol-3-yl)|-amide 5-(5,6,7,8- 0.85 - 0.88 (t, 2 H), 0.67 - 0.70 tetrahydropyridoyi3,4-4|pyrimidine-4-(t,2H)yloxy)-indole-1-carboxylic acid

IS

-090 E "still E (DMSO-dv) 6 parts/million 8.37 (5, ty - xx 1 N), 8.32 (a, 9-9.09 Hz, 1 N),

M. z M 7 M- 7.88 (a, 9U-3.79 Hz, 1 H), 7.39 (j,

Hm M 3-1.77 Hz, 1 H), 7.09 (aa, 9-9.09, 2.27 Hz, 1 H), 6.74 (5.1 134-0 M o nH n), 6.71 (a, ue379 hz, H), 3.931 21 - 3.98 (t, 5 H) 3.95 (5, C H),

P -methyl-5-(2,2,2-trifluoro-1-methoxy-1-3.18 (5 95.94 Hu, 2 H), 2.88 (i methylethyl)-1 H-pyrazole-3- yl|-amide 5- 95.68 Hz, 2 H), 1.84 (5, 3 n (5,6,7,8-tetrahydropyridoi|3,4- a|pyrimidin-4-yloxy)-indole-1 -carboxylic acid (mer) b part/million 8.53 (5.1

Ma o); x H), 8.31 (a, 9U-9.09 Hz, 1 H), 7.87 t If; where (a, 9U-3.79 Hz, 1 H), 7.42 (y,

M. 2 M and 9-2.27 Hz, 1 H), 7.11 (aa, y-8.97, 2.40 Hz, 1 H), 6.71 (a, 13KU and both 9-3, 79 Hz, 1 N), 6.33 (5, 1 N), 430.0

And 4.19 (a, 9-6.57 Hz, 4 H), 3.86 (5,

P -methyl-5-(1-methylcyclo-propyl)-1 n-Z H), 1 38 (in, Z H), 0.88 s 0.91 pyrazol-3-ylL|-amide 5-(6, 7-dihydro-5H- (t, 2 H), 0.79 - 0.83 (t, 2 n) pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid

E o o y (DMSO-dv) 6 parts/million 8.55 (5,

Ma X 1 H), 8.30 (a, 9-9.09 Hz, 1 H), (and Y 8.17 (a, 9U-3.79 Hz, 1 H), 7.45 (a,

M M z-d y-2.78 Hz, 1 H), 7.12 (aa, 134-MU M rya 9-9.09, 2.27 Hz, 1 H), 6.75 (5.1 501 ,9

H o nn H), 6.73 (a, 9U-3.79 Hz, 1 H), 4.06 (1-methyl-5-(2,2,2-trifluoro-1-methoxy-1- | 712 (t, 4 H) 3.91 (5, C H), methylethyl)-1H-pyrazol-3-ylI-amide 5-(6,7- | 217 (5, C H), 1.81 (5, With H) dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid (mer) b parts/million 8.36 (5.1 o H), 8.30 (a, 9U-8.84 Hz, 1 H), 7.85 g X (a, 9U-3.79 Hz, 1 H), 7.37 (j,

SshA- 9-2.27 Hz, 1 N), 7.07 (aa,

M M z-d 3-8.84, 2.27 Hz, 1 N), 6.69 (a, 134-X re 9U-3.79 Hz, 1 N), 6.32 (5.1 N) , 444 1

M o nn 3.93 (in, 2 H), 3.85 (5, C H), 3.16'

H (i, 9U-5.94 Hz, 2 H), 2.86 (i,

P-methyl-5-(1-methylcyclo-propyl)-1 H- 925.81 Hz, 2 H), 1.37 (5, C H), pyrazol-3-yl)|-amide 5-(5, 6,7,8- 0.87 - 0.90 (t, 2 H), 0.78 - 0.81 tetrahydropyridoyi3,4-4|pyrimidine-4- (t, 2 H) yloxy)-indol-1- carboxylic acid

SI g "CO (DMSO-4bv) 8.55 (5, 1 N), 8.26 1 7 (aa, 9U-6.32, 2.53 Hz, 2 N), 7.33

СХ У and (a, 9-8.84 Hz, 1 H), 6.83 (y, 93.79 Hz, 1 H), 6.65 (5, 1 H), 13 M o and 4.24 ( 8.2 N), 412(8.2 NN), 207 p. . . -2.25(t, 1 H), 0.84 -1.21 (t, (5-cyclopropylisoxazol-3-yl)-amide 4-4)chloro-5-(6,7-dihydro-5H-pyrrolo |3,4- a|pyrimidin-4-yloxy)-indole-1-carboxylic acid (DMSO-dv) parts/million 12.13 (Bu.

M 8; X 5.,1 H), 10.56 (brg. 5., 1 H), 8.52

TY dl (531N), 8.12-8.17 (t.2 N),

СХ in shi 7.05 (a, 94-8.84 Hz, 1 H), 6.81 (4, 93.79 Hz, 1 H), 6.29 (bBg. 5., 1

T13gya M on nu 407 -4y4(t,an)22-0709. . 2.25 (t, C H), 1.41 (5, C H), 0.91

15-(1-methylcyclopropyl)-1H-pyrazole-3- | 0.94 (t, 2 H), 0.76 - 0.79 (tyl|-amide 5-(6,7-dihydro-5H-pyrroloyi3,4- 2 n) I sho I I d|Ipyrimidine-4 -yloxy)-4-methylindole-1-carboxylic acid

SI

So b Z dl (DMSO-dv) frequent./million 8.55 (5, 1

M. 2 m Her 9 H), 8.23 - 8.32 (t, 2 H), 7.33 (a, 134-AA r M y-8.84 Hz, 1 H), 6.83 (y . Chloro- Nule (vanu Za (in, H) 5-(6,7-dihydro-5H-pyrrolo!|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid also)

Y 5 x r (DMSO-dv) freq./million 8.52 (5.1

M. Z M (o; H), 8.11 -8.16 (t, 2 H), 7.09 (y, p M y5-9.09 Hz, 1 H), 6.88 (a, 9 -3.79 134-AB M M Hz, 1 N), 6.69 (5.1 N), 4.14(5.2| 419.18 n on N), 4.08-410(t, 2 H), 3.11 (i, (5-isopropylisoxazol-3-yl)-amide 5-(6.7-|9-6.57 Hz, 1 H), 2.24 (5.3 H), dihydro -5H-pyrrolo|3,4-4|pyrimidine-4- 1,29 (а, У-7,07 Hz, 6 H)yloxy)-4-methylindole-1-carboxylic acid

M., O i - xx years (DMSO-4v) freq./million 8.52 (5, 1

M. Zh M |e; H), 8.10 - 8.15 (t, 2 H), 7.09 (y, ra M y-8.84 Hz, 1 H), 6.87 (y, 9-3.79 134-АС M M Hz, 1 N), 6.65 (5.1 N), 4.14 (5.2| 417.16 n o n N), 4.06 - 4.10 (t, 2 N), 2 .24 (5, (5-cyclopropylisoxazol-3-yl)-amide 5-Z H), 2.17 (5.1 H), 1.06 -1.11 (6,7-dihydro-5H-pyrrolo| 3,4-a|pyrimidine-4- (t, 2 H), 0.92 - 0.96 (t, 2 H) yloxy)-4-methylindole-1-carboxylic acid

(F "more; (DMSO-dv) freq./million 8.55 (5, 1

That is: x - H), 8.27 (aa, U-6.06, 2.27 Hz, 2

M. Zh M (o; H), 7.33 (a, 9-9.09 Hz, 1 H), 6.83 -oi (a, 9-3.79 Hz, 1 H), 6.69 ( 5.1 N), 134-Ao M chm" 422 (8.2 N), 413 (8.2 N), 31 007392

Hn on (quintet, U-6.88 Hz, 1 H), 1,29 (B-isopropylisoxazol-3-yl)-amide 4-chloro-5-| (9, y-6.82 Hz, 6 H) (6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid

M (c) gai SI SE, dhE (DMSO-dv) part/million 8.53 (5.1 va y and H), 811 - 8.16 (t, 2 H), 7.10 (4.4 -9.09 Hz, 1 N), 7.05 (5, 1 N), 1ZA-LE and o B 6.89 (a, 923.79 Hz, 1 N), 4.17 (5.789

I5-(1-trifluoromethyl-cyclopropyl)-: in vot M (5, C H), isoxazol-3-yl|-amide 5-(6,7-dihydro-5H-' ' ' pyrrolo|3,4-4 |pyrimidin-4-yloxy)-4-methylindole-1-carboxylic acid

М.

Between M not) H), 7.04 - 7.07 (t, 2 H), 6.87 (4, at 3.79 Hz, 1 H), 3.89 (a, with -10.36 Hz, 2 H), 3.00 (a9a, 13A-AE M OH 9-10.11, 6.32, 4.04 HC, 1 H), 513.18 4-methyl- (5-(1-trifluoromethyl- 2 .90 (da, )-16.80, 3.41 Hz, 1 H), cyclopropyl)-isoxazol-3-ylI-amide 5-((5)- | 292 - 2.45 (t, 1 H), 2.22 (5, C b-methyl-5,6,7,8-tetrahydropyridoyiZ3,4-NO, 1.52 - 1.60 (t, 4 H) 1.23 (9, aIpyrimidin-4-yloxy)-indole -1-carboxylic | 79.32 Hz, C H) acid (DMSO-dv) parts/million 8.36 (5, 1

M (F) H), 8.10 - 8.14 (t, 2 H), 7.05 (a, pe U 2 459.09 Hz, 1 H), 6.86 (a, 9-3.79

M. 2 M io); HC, 1 H), 6.65 (5, 1 H), 3.88 (4,

X-M 929.60 Hu, 2 H), 2.94 - 3.02 (t, 134-AS M z, He) and 1 H), 2.88 (ai, 9U-16.93, 3.79 Gu, 445.19

H 1 H), 2.37 (ad, 2-16.93, 10.61 4-methyl-(5-cyclopropyl-isoxazol-3-yl)-Hz, 1 H), 214 -2.23(t, 4 H), amide 5-((5)-6-methyl-5,6,7,8-tetrahydro-1,22 (a, U-6,06 Gu, Z H), 1,06 - pyrido|3 ,4-a-pyrimidin-4-yloxy)-indole-1- | 1511 (t, 2 H), 0.92-0.96 (t, 2 carboxylic acid H). (DMSO-dv) parts/million 8.36 (5, 1 more; H), 8.09 -- 8.16 (t, 2 H), 7.05 (4, pe U 2 4-8.84 Hz, 1 N), 6.86 (a, 9-3.79

M. M more; Hz, 1 N), 6.67 (5, 1 N), 3.80 -

Chm 3.96 (t, 2 H), 2.87 (8, 1 H), 2.67 134-AN M t, o nn (Y, 9-1.89 Hu, 1 H), 2.30 - 2.40 459.21

H (t, 1 H), 2.22 (5, C H), 1.46 (5, C 4-methyl- (5-(1-methylcyclopropyl)-NO, 1.23 (a, U-6, 32 Hz, C H), 1.11 isoxazol-3-ylI-amide 5-((5)-b-methyl- -118 (t, 2 H), 0.90 - 0.97 (t, 5.6 ,7,8-tetrahydropyridoyiZ3,4-4|pyrimidine-2H)4-yloxy)-indole-1-carboxylic acid o (DMSO-dv) parts/million 8.36 (5, 1

E X H), 8.09 - 8.16 (t, 2 H), 7.05 (y, ke y-8.84 Hz, 1 H), 6.86 (y, 9U-3.79

SA U. IR Hz, 1 H), 6.69 (5, 1 H), 3.81 - ., M 3.95 (t, 2 H), 3.10 (y, 9-7.07 13A- LI m" on HC, H), 2.99 (bg. 5.1), 2892

H (a, 9-14.65 Hz, 1 H), 2.31 - 2.43 4-methyl-(5-isopropylisoxazol-3-yl)-amide (t, 1 H), 2.22 (5, With H), 1.29 (y, 5-((5)-6-methyl-5,6,7,8-4-6.82 Hz, 6 H), 1.23 (a, 9U-6, 32 tetrahydropyridoyi3,4-4|pyrimidine-4-Hz, C H) yloxy)-indole-1-carboxylic acid

M.,O0 (DMSO-dv) parts/million 8.55 (5, 1

Tj t If; where NU, 8.25 (y, 9-9.09 Hz, 1 H), 8.07

M. and M |v) (a, 9-3.54 Hz, 1 H), 7.48 (y, ra M y-2.27 Hz, 1 H), 7.15 (aa, 134-Au) their o and 98.97, 2.40 Hz, 1 H), 6.78 (y, 417.03 93.54 Hz, 1 H), 4.10 (a, (5-cyclopropyl-4-methyl-isoxazole -Z-yl)- | )-14.91 Hz, 4 H), 2,12-2,19 amide 5-(6,7-dihydro-5H-pyrroloi|3,4- (t, 1 H), 1.95 (with, with H), 0.94 - a|pyrimidin-4-yloxy)-indole-1-carbon | 41.10 (t, 4 N) acid (DMSO-dv) part/million 8.55 (5.1 g If; I H), 8.24 (a, -8.84, 1 N), 8.23 (in,

M. 2 M and |c) 1 H), 8.07 (a, 9-3.79 Hz, 1 H), ra M 7.48 (a, 9-2.27 Hz, 1 H), 7, 14 134-AK M o! her (aa, 9u-8.97, 2.40 Hz, 1 N), 6.79 433.19

H (a, 9-3.79 Hz, 1 H), 4.11 (a, (B-tert-butyl-4-methylisoxazol-3-yl)- 915.16 Hz, 4 H), 1.98 ( 5, 3 H), amide of 5-(6,7-dihydro-5H-pyrrolo|3,4- 1,38 (5, 9 H). a|pyrimidin-4-yloxy)-indole-1-carboxylic acid also ) si (DMSO-dv) parts/million 8.58 (5.1 and t If; where H), 8.29 (0.9U-9.09 Hz, 1 H), 8.04

M. and M |e; (a, 9-3.79 Hz, 1 H), 7.48 (y, p M y-2.27 Hz, 1 H), 7.14 (aa, 134-AG. y o y 98.97, 2.40 Hz, 1 H), 6.77 (y, 437.11 93.54 Hz, 1 H), 4.15 (y, (4-chloro-5-cyclopropylisoxazol-3-yl)-y-13 ,89 Hz, 4 H), 2.17 - 2.24 amide 5-(6,7-dihydro-5H-pyrroloi|3,4- (t, 1 H), 1.07 -1.20 (t, 4 H) a|pyrimidin-4-yloxy)-indole-1-carboxylic acid o) (DMSO-dv) parts/million 8.55 (5, 1 and 7 If; d H), 8.24 (j, 2-9.09 Hz, 1 N), 8.06

M. Ж M |c) (a, 9-3.79 Hz, 1 H), 7.48 (j, p M y-2.27 Hz, 1 H), 7.14 (aa, 134-AM M about them 98.97, 2.40 Hz, 1 N), 6.79 (y, 431.18

H u3-3.54 Hz, 1 N), 4.08 - 4.14 (t,

14-methyl-5-(1-methylcyclopropyl)-4H), 1.96 (5, C H), 1.41 (5, C H), isoxazol-3-yl|-amide 5-(6 ,7-dihydro-5H- 1.03 (y, 9-2.27 Hz, 2 H), 0.83 - pyrrolo|3,4-a|pyrimidin-4-yloxy)-indole-1- | 0.87 (t, 2 N). carboxylic acid o (DMSO-dv) parts/million 8.56 (5.1 g CO H), 8.28 (5.1 H), 8.03 (a, 9U-3.79 and Hz, 1 H ), 7.47 (9, 9u-2.53 Hz, 1 134-AM AH Mi - H), 7.13 (ad, 929.09,2.27 Hz,1 | 79914

Mrya NU, 6.77 (a, 9-3.79 Hz, 1 H), 4.10

N o nn - 415 (t, 4 N), 1.43 (5.9 N)

(b-tert-butyl-4-chloroisoxazol-3-yl)-amide 5-(6,7-dihydro-5H-pyrrolo!|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid h

Mao x o (DMSO-ov) parts/million 8.55 (5.1 (i so H), 8.25 (5.1 N), 8.22 (5.1 N),

Mo U. here 8.05 (a, 9U-3.54 Hz, 1 H), 7.48 (a, 9-2.27 Hz, 1 H), 7.15 (aa, 13y-Ao and on Ch -8.84,2.53 Hz, 1 H),6.79(4, | 799.20 (5-tert-butyl-4-methoxymethyl-isoxazole- 3.9 Hz, 1 H), 432 (5, 2 N), . and .: 4.13 (5, 2 N), 4.09 (y, 9-1.77 Hz,

3-yl)-amide 5-(6,7-dihydro-5H-pyrroloi|3,4-2H), 319 (5,3H), 1,40 (5,9H) a|pyrimidine-4- yloxy)-indole-1-carboxylic acid

M (in) SI (DMSO-dv) parts/million 8.57 (5.1 in If; r H), 8.28 (4.4-9.09 HC, 1 H), 8.02

M. 2 M no |v) (a, 9U-3.79 Hz, 1 H), 748 (a, ra M 9-2.27 Hz, 1 H), 7.14 (aa, 134-AR their o their 3-8.84, 2.27 Hz, 1 H), 6.77 (a, 451.12 3-3.54 Hz, 1 H), 4.14 (a, (d-chloro-5-( 1-methylcyclopropyl)-Y-12.88 HC, 4 H), 1.48 (5.3 H), isoxazol-3-yl|-amide 5-(6,7-dihydro-5H-1,21-1 ,25 (t, 2 N), 0.93 - 0.96 pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-(t, 2 N).carboxylic acid o (DMSO-dv) freq./million 10.69 (5.1 g x H), 8.35 (5.1 H), 8.18 (9.9-3.79 7 -k Hz, 1 H), 8.13 ( a, 9U-9.09 Hz, 1

M M in H), 7.78 (a, 4-2.53 Hz, 1 H), 134-AO .., rya 7.01s (a, 9U-8.84 Hz, 1 H), 6.80 (a, 4602

MO" o n uU-3.79 Hz, 1 N), 6.52 (y, 9-2.53 "

H Hz, 1 H), 3.82 - 3.93 (t, 2 H), 4-methyl-(1-tert-butyl-1 H-pyrazol-3-yl)- | 2.82 - 2.95 (t, 2 H), 2.31-2.42 amide 5-((5)-6-methyl-5,6,7,8- (t, 1 H), 2, 21 (5, C H), 1.54 (5,9 tetrahydropyridoyi3,4-4|pyrimidine-4-NH, 1.22 (a, 9-6.32 Hz, C H)yloxy)-indole-1- carboxylic acid also and (DMSO-dbv) parts/million 8.40 (5.1 g 5 x H), 8.29 (a, 9U-8.84 Hz, 1 H), 8.18

M. Ж M 7 M, (a, 9U-3.54 Hz, 1 H), 7.42 (y,

M M 9-2.02 Hz, 1 H), 7.06-7 24 (t, 2 134-AB mo M H), 6.74 (a, 9-3.79 Hz, 1 H), 4, 18 4861

MO o nH - 4.37 (t, 2 H), 3.84 - 3.93 (t, ' , 2 H), 2.95- 2.97 (t, 1 H), 2.85 (1- ethyl-5-trifluoromethyl-1H-pyrazole-3-(a, 916.67 Hz, 1H), 2.29 - 2.35 yl)-amide ((5)-6-methyl-5,6,7 ,8- (t, 1 H), 1.38 -1.42 (t, C H), tetrahydropyridoyi3,4-4|pyrimidine-4- 1,21 (a, 9-6,32 Hz, C H) yloxy)-indole-1-carboxylic acid

RE g o X R (DMSO-av) freq./million 11.02 (bg. in YasK- 8., 1 N), 8.36 (5, 1 N), 8.02-8.21

M M 5 (t, 2 H), 6.96-7.14 (t, 2 H), 134-A5. p 6.85 (a, 9-3.79 Hz, 1 N), 3.5 (5, 486.0

MO" o n Z H), 3.88 (a, U-9.60 Hz, 2 H), "

H 2.93-3.04 (t, 1 H), 2.89-2.93 (t, (1-methyl-o-trifluoromethyl-1H-pyrazole-3- | 1 H), 2.36 - 2 .40 (t, 1 H), 2.22 yl)-amide 4-methyl-5-((5)-b-methyl-5,6,7,8- (v, 3 H), 1.22 ( 0.95-6.32 Hz, with H) tetrahydro-pyridoyi3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid

(DMSO-dv) freq./million 10.63 (5.1

H), 8.39 (5, 1 H), 8.28 (a, 9U-8.84 o Hz, 1 H), 8.18 (a, 9U-3.79 Hz, 1 ha X H), 7.39 (a, 9-2.27 Hz, 1 H), 7.07 s - (ad, 9U-8.97, 2.40 Hz, 1 H), 6.68

M M zdi (a, 9U-3.54 Hz, 1 H), 6.16 (5.1 H), 134-AT .., rya 4.76 (quintet, U-6.57 Hz, 1 H) , 472.0

MO o nn 3.77-3.96 (t, 2 H), 2.90-3.03 (t, '

H 1 H), 2.84 (da, uU-16.80, 3.66 Hz, (5-cyclopropyl-1-isopropyl-1 H-pyrazole-3-| 1 H), 2.33 (ad, U -16.04, 10.23 yl)-amide 5-((5)-6-methyl-5,6,7,8-HC, 1 H), 1.86-1.98 (t, 1 H) , tetrahydropyrido|3,4-a|pyrimidine-4- 1,42 (a, 9-6,57 Hz, 6 H), 1,21 (y, yloxy)-indole-1-carboxylic acid y-6,32 Hz, Z H), 0.87-1.03 (t, 2), 0.59-0.76 (t, 2 H

M (c) (DMSO-dv) parts/million 8.36 (5, 1 t If; Ge o H), 8.30 (a, 9U-8.84 Hz, 1 H), 7.85

M.O 22 M no M (a, 9U-3.54 Hz, 1 H), 7.37 (y,

Chm M 9-2.27 Hz, 1 H), 7.07 (aa, t, 3-8.97, 2.15 Hz, 1 H), 6.68 (a, 13A-Au and on 9-3 ,28 HC, 1 H), 6.37 (in, 1 H), 460.2 (1-tert-butyl-5-methyl-1 H-pyrazol-3-yl)- 3.98 (y, 554, 55 Hz, 2 H), 2,94-amide 5-((5)-6-methyl-5,6,7,8-Z (t, 2 H), halo (t, Z tetrahydropyridoyi3,4-4| Pyrimidine-4-NU, 1.63 (5.9 H), 1.92 (0.9-6.32 yloxy)-indole-1-carboxylic acid Hz, 3 H).

Example 135 135-А. (5-Cyclopropylisoxazol-3-yl)-amide (-)-5-((5)-7-acetyl-b-methyl-5,6,7,8-tetrahydropyridoyl3,4-a|pyrimidin-4-yloxy) -indole-1-carboxylic acid. (6) your f; and ! 7

M. m her 8 4 khu m on o

Acetic anhydride (0.084 ml, 0.894 mmol) was added to a solution of the compound of example 56-5 (0.350 g, 0.813 mmol), E18VM (0.57 ml, 4.07 mmol) and DXM (5 ml). After 0.5 hours the solution is concentrated and the residue is partitioned between DCM and a saturated solution of MansSoOz. The organic layer is washed with saline solution. After drying, the organic layer is concentrated and the residue is purified using

KFH (1-10 96 MeOnH/DHM) and get the desired compound. MS (IER) t/2 473.2 (M'-1); at 27 "C in a solution in DMSO-6, the compound of example 135-A exists in the form of a mixture of reversible amide isomers. If we are not limited by theoretical considerations, then we can assume that the inhibited rotation around the nitrogen-carbonyl bond leads to two environments of some protons, which are characterized by different magnetic characteristics. "H NMR is taken at 80"C, which is higher than the temperature at which individual peaks of the "H reversible isomer merge. (400 MHz, DMSO-av) b frequency/million 10.95 (Bg. 5., 1 H), 8.50 (5, 1 H), 8.28 (y, 9-8.97 Hz, 1 H), 8.13 (a, 9U-3.66 Hz, 1 H), 7.45 (y, 9-2.27 Gu, 1 H), 7.14 (da, U-9.03, 2 ,34 Hz, 1 N), 6.73 (a, 9-3.66 Hz, 1 N), 6.59 (5, 1 N), 4.61 - 5.43 (t, 2 N), 4 .22 (horn. 5., 1 H), 2.99 (Bri. 5., 1 H), 2.79 - 2.89 (t, 1 H), 2.11-2.19 (t, 4 Н), 1.17 (a, 9-7.33 Hz, З Н), 1.06-1.13 (t, 2 Н), 0.91-0.96 (t, 2 Н).

The following compounds are obtained by a similar method. Such compounds are also obtained from the appropriate carboxylic acid and amine using reagents used in coupling with the formation of a peptide bond (for example, NATI, see example 40), or using the appropriate carboxylic acid chloride. The compound of example 135-BM is obtained by a similar method using ethyl chloroformate. In examples 135-Y, ), 1, P, AS, АЮ, АЕ, АЕ, АС, AN, cleavage of the BOC group from the nitrogen atom with the subsequent formation of an amide is carried out by treating the starting compound with TFC in DCM, as described in the previous examples.

MORE and MS (ER)

C siyuunyunnn 00 nyazhesyumo 1

(DMSO-dv) 6 ppm 11.22 (5,

Mo); 1 N), 8.52 (rg. 5.), 8.28 (a, 5-8.8 and IF; du Hz, 1 N), 8.16 (a, 9-3.5 Hz, 1 N ),

M. Zh Myaiv) 7.46 (a, 9-2.5 Hz, 1 H), 7.15 (yes, oy rya M 99.0, 2.4 Hz, 1 H), 6.76 ( 9, 9-3.3 va about LV HC, 1 N), 6.65 (5, 1 N), 5.16 - 1358 A. 5.22 (t), 5.13 (s), 4.73 -- 4.79 473.0

Ge) (t), 4.48 - 4.63 (t), 4.04 (9), (B-cyclopropylisoxazol-3-yl)-amide (4)-5-. 204 - 3.15 (t), 2.78 - 2.88 (t), (I-7-acetyl-b-methyl-5,6,7,8- 2.09 - 2.23 (t), 1, 21 (a, 5-6,6 tetrahydropyridoi3,4-4|pyrimidine-4-Hz, 2 H), 1.03 - 1.13 (t, C H), yloxy)-indole-1-carboxylic acid 0, 89 -0.98 (t, 2 N) (110 "C; DMSO-av) b parts/million

M. she; Ce 10.33 (rg. 5., 1 H), 8.50 (5, 1 H), and - 8.29 (y, U-8.97 HC, 1 H), 8.11 (4,

M. 22 M no o 93.79 HC, 1 H), 7.45 (y, 9-2.27 4 rya M HC, 1 H), 7.14 (da, U-8.97, 2.40 ke o nn HC, 1 H), 6.96 (5, 1 H), 6.73 (y, 135-065 AJ. 93.66 Hz, 1 H), 4.98 (y, 9-19.71 541.1 o HC, 1 H), 4.87 (Brg. 5., 1 H), 4.26

I5-(1-trifluoromethyl-cyclopropyl)-(a, t Hz, 1 H), troisoxazol-3-ylI-amide 5-((5)-7-acetyl-b-(7 1 H), 2, 88 (Bg. 5., 1 H), 2.115 methyl-5,6,7,8-tetrahydropyrido|3,4- (5, C H), 1.49 -1.60 (t, 4 H),

Pyrimidin-4-yloxy)-indole-1-carboxylic acid 1,19 (a, 9-6,82 Hz, З H) acid

Mo (DMSO-dv) 6 parts/million 11.22 (in, ha If; 1 N), 8.51 (8, 1 N), 8.28 (4, 9-9.

M. Zh M and Ge, Hz, 1 N), 8.16 (a, 9-3.5 Hz, 1 N),

IR 7.47 (a, 9-23 Hz, 1 N), 7.16 (da, -, Hm 99.0, 2.4 Hz, 1 N), 6.76 (0, 9-3.5 135 -038 MO" o n HC, 1 N), 6.65 (5.1 N), 4.97 - 499 1 5.24 (t), 4.52 - 4.74 (t), 4.03 - " at 4.23 (t), 2.99 - 3.17 (t), 2.76 - 2.96 (t), 2.14-2.23 (t), 2.02 - (5-cyclopropylisoxazole -3-yl)-amide 5- 2.16 (t), 1.19 --1.32 (t), 1.05 - ((5)-7-cyclopropane-carbonyl-b6-methyl- 1.13 (t), 0.91 - 0.98 (t), 0.81 - 2,6,7,8-tetrahydropyridoi|3,4-a|pyrimidine- | 0.89 (t), 0.71 - 0 ,81 (t) of 4-yloxy)-indole-1-carboxylic acid at (110 "C; DMSO-dv) 5 parts/million ha IF; SE, 10.98 (rg. 5., 1 H), 8 .50 (5, 1 N), hundred 8.28 (a, 9-8.84 Hz, 1 N), 8.11 (a,

M M s 93.54 Hz, 1 N), 7.46 (y, 9-1.77 . rya Hz, 1 N), 7.15 (da, 9U-8.84, 1.77

MO o nn HC, 1 H), 6.96 (5, 1 H), 6.74 (y, y-3.54 Hz, 1 H), 5.02 (a, U9-18.69 135-E ? about Hz. H),492(bg5.,1H),4.25 | 832 (a, 9-18.95 Hz, 1 H), 2.95 - 3.05 (t, 1 H), 2.83 (bBg. 5., 1 H), 2.35 (5-(1 -trifluoromethyl-cyclopropyl)-(a, 9-5.68 Hz, 2 H), 2.07 -2.17 isoxazole-3-ylyl-amide 5-((5)-6-methyl-7-(3- |(t, 1 H), 1.48 - 1.62 (t, 4 H), methylbutyryl)-5,6,7,8- 1.19 (y, 5-6.69 Hz, C H), 0.98 (4, tetrahydropyridoyiZ,4-4|pyrimidine-4- 925.05 Hz, 6 H) yloxy|-indole-1-carboxylic acid ee and; Se (DMSO-dv) 6 ppm 11.43 (5, i du 1 H), 8.49 (5, 1 H), 8.29 (a,

M. M 6 9-9.09 Hz, 1 N), 8.16 (d, 9-3.54 rya M Hz, 1 N), 7.48 (a, 9-2.27 Hz, 1 N) , ke o nn 7.16 (aa, U-8.97, 2.40 Hz, 1 H), 7.04 (5, 1 H), 6.77 (9, 9-3.79 Hz, 185- E o 1 n), 510 (a, 9-19.20 Hz, 1 H), 583.2 4.94 - 5.06 (t, 1 H), 4.17 (a,

IB-(1-trifluoromethyl-cyclopropyl)-y-19.20 Hz, 1 NI, 2.93 - 3.04 (t,

IS . . 1 H), 2.81 (a, 9-16.93 Hz, 1 H), isoxazole-3-ylI-amide 5-((5)-7-(2,2- 1.53 - 1.60 ( t, 4 H), 1.27 (v, 9 dimethyl-propionyl)-b-methyl-5,6,7,8-n 1 21 (a d-6 82 g З n)' tetrahydropyridoiYZ,4-4| pyrimidine-4-shi'' c, yloxy|-indole-1-carboxylic acid

Me 8; X (DMSO-dv) 6 ppm 11.22 (5, and If; for 1 N), 8.50 (5, 1 N), 8.28 (and, U-8.8

Mi 2 M i iv) Hz, 1 H), 8.16 (a, 9-3.8 Hz, 1 H), rya M 7.45 (a, 9-23 Hz, 1 H), 7.14 ( yes, o nn 99.0, 2.4 Hz, 1 N), 6.76 (0, 9-3.5 135-0 A. Hz, 1 N), 6.65 (5, 1 N), 4 .59 - 459.2

Ge) 4.71 (t, 2 H), 3.81 (, 9-5.8 Hz, 2 (5-cyclopropylisoxazol-3-yl)-amide 5-(7- Nu, 2.76 -2.98 (t, 2 H), 2.08 - acetyl-5,6,7,8-tetrahydropyridoyi3,4- 2.26 (t, 4 H), 1.05-1.15 (t,2 a|pyrimidine-4- yloxy)-indole-1-carboxylic H), 0.89 - 0.98 (t, 2 H) acid

M (c)

Y where x (DMSO-dv) 6 parts/million 11.27 (5,

M. is M and (o; 1 H), 8.48 (5, 1 H), 8.29 (a, U-8.8

X M Hz, 1 N), 8.16 (a, 9-3.8 Hz, 1 N),

M 7.45 (a, 9-2.5 Hz, 1 N), 7.14 (yes, 135-N M o n 9-8.8,2.3 Hz, 1 N), 6.76 (a ,9-3,8 | 475,2

AH. HC, 1 H), 6.68 (5, 1 H), 4.62 (5, 1 iv) H), 3.75 - 3.85 (t, 2 H), 2.89 - (5-tert -butylisoxazol-Z-yl)-amide 5-(7- 2.97 (t, 2 H), 2.15 (5, C H), 1.34 acetyl-5,6,7,8-tetrahydropyridoi|Z3 ,4-(5.9 N) a|pyrimidin-4-yloxy)-indole-1-carboxylic acid

Mao x Se. (DMSO-av) b freq./million 8.50 (5.1 (th hundred N), 8.35 (a, U-8.84 Hz, 1 N), 8.14

М M - (a, 9-3.54 Hz, 1 H), 7.44 (y, , ря M 9-2.27 Hz, 1 H), 7.12 (aa, U-8.84,

Me o nn 2.27 Hz, 1 H), 7.03 (5, 1 H), 6.70 (a, 9-3.54 Hz, 1 H), 5.18 (bg. 5.,2 185 sia N),425 (bg. 8.1 ),2.93-3.20 | 781

MH (t, 1 H), 2.80 (a, 9-16.67 Hz, 1 ? | H), 1.45 - 1.60 (t, 5 H), 1.20 (a, (5- (1-trifluoromethyl-cyclopropyl)-y-6.57 Hz, C H), 0.94 - 1.04 (t, isoxazol-3-yl|-amide 5-I(5)-7-(1- 1 H), 0.81 - 0.90 (t, 1 H), 0.65 - aminocyclo-propanecarbonyl)-6-methyl- 0.79 (t, 2 H) 5,6,7,8-tetrahydropyridoyiZ,4 -4|pyrimidine-4-yloxy|-indole-1-carboxylic acid

We are about SE

What's up with her?

If; hundred (DMSO-dv) 6 parts/million 8.50 (5, 1

Mo M - H), 8.33 (4, 4-8.84 Hz, 1 H), 8.15, rya M (a, 9U-3.79 Hz, 1 H), 7.45 (y,

Me o nn 9-2.27 Hz, 1 H), 7.13 (aa, U-8.97, 2.40 Hz, 1 H), 7.03 (5, 1 H), 6.73 1357 o (4, 4-3.54 Hz. 1 N), 5.48 (bi. 5.,2|...29939

MH H), 4.21 (Bg. 5., 1 H), 3.00 (Bg. 5., 2 , 1 H)U, 2.78 (a, 9-17.18 Hz, 1 H),

I5-(1-trifluoromethyl-cyclopropyl)- 1.50 - 1.59 (t, 4 H), 1.42 (5, 6 isoxazol-3-yl|-amide 5-(5)-7-(2- amino-2-H), 1.20 (a, 9U-6.82 Hz, 3 n methylpropionyl)-6-methyl-5,6,7,8-tetrahydropyridoyiZ,4-4|pyrimidin-4-yloxy|I -indole-1-carboxylic acid (DMSO-dv) 6 ppm 11.22 (5, o 1 N), 8.50 (Bg. 5., 1 N), 8.29 (a, ge x 3 -91 Gu, 1 N), 8.15 (y, 9-3.5 Hz, o 1 N), 7.46 (a, 9-23 Hz, 1 N), 7.14

M M si (ai, 9U-9.0, 2.4 Hz, 1 H), 6.75 (a, . rya 9U-3.5 Hz, 1 H), 6.65 (5, 1 H), 5.20

MOU o n - 5.29 (t), 5.16 (a, 9U-18.9 Gu), 135-Ka 4.81 (a, 9-18.4 Hz), 4.61-4.72 499 ,1 o, (t), 4.49 (a, 9U-19.2 Hz), 4.05 (a, 9-19.2 Hz), 2.97 - 3.09 (t), 2.75

Also II I - 2.88 (t), 2.29 -2.40 (t), 212 (5-cyclopropylisoxazol-3-yl)-amide 5-(5)4.. 2.22 (t, 1 H ), 1.98 -2.11 (t, 1 b-methyl-7-(3-methylbutyryl)-5,6,7,8-H), 1.20 (a, 96.1 Hz, 2 H) .

M. ,;0 (DMSO-dv) 6 parts/million 8.51 (5.1 "me If; and H), 8.34. (4.4-91 Hz, 1 H), 8.13

M. and M and |c) (a, 9U-3.5 Hz, 1 N), 7.43 (a, U-2.3 r M Hz, 1 N), 7.10 (aa, 9U-9 ,0, 2.4 Hz, if 1 N), 6.69 (a, 9U-3.5 Hz, 1 N), 6.63 135-12 (5, 1 N), 5.07 - 5 .53 (t), 4.65 - 4881 o 4.81 (t), 4.37 - 4.61 (t), 4.04 - " 4.19 (t) 3.43 - 3.69 (t ), 2.99 -

MH, 3.18 (t), 2.76 - 2.91 (t), 2.07 - (5-cyclopropylisoxazol-3-yl)-amide 5-((5)- 2.20 (t), 1 .09 - 1.26 (t), 1.02 - 7-(2-aminoacetyl)-6-methyl-5,6,7,8- 1.09 (t, 2 H), 0.86 - 0, 94 (t, 2 tetrahydro-pyrido|3,4-4|pyrimidine-4-di;yloxy|-indole-1-carboxylic acid "more; (DMSO-dv) 6 parts/million 11.22 (5, ty with x 1 H), 8.50 (Bg. 5., 1 H), 8.28 (y,

M. z M y (o; 3-9.1 Gu, 1 H), 8.16 (y, 9U-3.8 Hz, ra z 1 H), 7.46 (a, 9-23 Hz, 1 H), 7.15 z, M (aa, 9-9.0, 2.4 Hz, 1 H), 6.75 (a, 135-Me M On 9U-3.5 Hz, 1 H), 6 ,65 (5, 1 H), 5,10 5Oi 1 - 5,31 (t), 4,87 (0), 4,66 - 4,78 " shk (t), 4,54 (4), 4 .06 (9), 2.94 - 3.13 (t), 2.76 -2.92 (t), 2.10 - (5-cyclopropylisoxazol-3-yl)-amide 5- 2.24 (t ), 1.23 (d, 9-66 Hz, 2 H), ((5)-7-isobutyryl-b-methyl-5,6,7,8- 1.04 -1.13 (t), 0 .97 - 1.03 (t), tetrahydro-pyridoY3,4-4|pyrimidine-4- 0.88 - 0.97 (t, 2.H) yloxy)-indole-1-carboxylic acid ha o X (DMSO - sv) b freq./million 11.04 in so (eg. 5., 1 H), 8.48 (5, 1 H), 8.30

M M s IR (a, 9-91 Hz, 1 N), 8.17 (a, 9U-3.8

Khm Hz, 1 N), 7.45 (a, 9-2.3 Hz, 1 N),

M o nn 7.13 (а, 9-91 Hz, 1 H), 6.76 (а, 135-М 93.5 Hz, 1 H), 6.68 (5.1 НН), 4.64| 560.3 obi (5, 2 N), 3.84 (d, U9-6.0 Hz, 2 N),

C 2.93 (Her, 9-4.9 Hz, 1 H), 2.71 -

I I 2.84 (t, C H), 2.52 -2.66 (t, 6 (5B-tert-butylisoxazol-3-yl)-amide 5-I(7-(3- H), 1, 34 (z, 9 H), 0.90 - 1.03 (t, diethylaminopropionyl)-5,6,7,8-vn) tetrahydropyridoy33,4-4|pyrimidin-4-yloxy|I-indole-1-carbon acid m. o (DMSO-dv) 6 ppm 10.55

TY where x (g. 5., 1 H), 8.47 (5, 1 H), 8.30

M. and M In SMN (a, 9-8.8 Hz, 1 N), 8.17 (a, 9U-3.3

X M Hz, 2 N), 7.42 (5.1 N), 7.10 (a,

M U-7.8 Hz, 1 N), 6.65 - 6.73 (t, 1 135-0 M on H), 6.30 (5.1 N), 4.61 (5.2 N) , 472.3

AH. 3.74 - 3.85 (t, 2 H), 2.88 --. 2.97 iv) (t, 1 H), 2.76 - 2.84 (t, 1 H), (5-(1-methylcyclopropyl)-1H-pyrazole-3-|2.15 (5, C H ), 1.41 (z, C H), 0.89 - yl)|-amide 5-(7-acetyl-5,6,7,8- 0.97 (t, 2 H), 0.73 - 0.80 (t, 2 tetrahydropyridoyi3,4-4|pyrimidin-4-nyloxy)-indole-1-carboxylic acid (c) is Me If; Ac (80 "C DMSO-d5) b part./million

M. and M 9) 8.51 (5.1 N), 8.35 (y, 9-8.84 Hz, ra M 1 N), 8.12 (a, 9U-3.66 Hz, 1 N ), m» o y 7.42 (a, 9-2.27 Hz, 1 H), 7.10 (aa, 9U-8.91, 2.34 Hz, 1 H), 6.98 135-Р5 57 (5, 1 H), 6.68 (a, 9U-3.66 Hz, 1 H), 556.1 5.28 (rg. 5., 2 H) 4.94 (Bg. 5... 2

МН, Н), 416-441 (t, 1 Н), 2.96 -

I5-(1-trifluoromethyl-cyclopropyl)- 3.01 (t, 1 H), 2.79 - 2.92 (t, 1 isoxazol-3-ylI-amide 5-|(5)-7-(2- NU, 1.47 -1.57 (t, 4 H), 1.19 (a, aminoacetyl)-6-methyl-5,6,7,8- 97.07 Hz, 3 H). 4-4|pyrimidin-4-yloxy|-indole-1-carboxylic acid "still SE (100 "C DMSO-dv) 6 parts/million ty s xx EC! 11.04 (g. 5., 1 N) , 8.50 (5.1 N),

M r M ke 8.28 (a, 9-8.84 Hz, 1 H), 8.12 (j,

CI 93.79 Hz, 1 N), 7.46 (y, 9-2.15 , X-m Hz, 1 N), 7.15 (da, 9U-8.84, 2.27

MO" o n Hz, 1 N), 6.97 (5, 1 N), 6.75 (a, 135-605 93.66 Hz, 1 N), 5.05 (a, U-18.95 569 ,2 and, HC, 1 H), 4.94 (bBg. 5., 1 H), 4.26 (a, 9-18.95 Hz, 1 H), 2.97 - 3.05

I5-(1-trifluoromethyl-cyclopropyl)- (t, 2 H), 2.81-2.91 (t, 1 H), isoxazol-3-ylI-amide 5-((5)-7-isobutyryl- | 1.47-1.61 (t, 4 H), 1.20 (y, b-methyl-5,6,7,8-tetrahydro-pyridoY3,4-|9-6.69 Hz, 3 H), 1,10 (its, 9-7,14 9|pyrimidin-4-yloxy)-indole-1-carboxylic acid| Hz, 6 H) acid o (80 "С DMSO-ав) 6 parts/million gai X CE. 11.17 (Bg. 5., 1 H), 8.51 (5.1 H), p 7o 8.30 (a, 9-8.97 Hz, 1 H), 8.13 (a,

M M am 93.79 Hz, 1 N), 7.46 (y, 9-2.15 .,, Khm Hz, 1 N), 7.15 (da, U-8.97, 2.40

MO" o n HC, 1 H), 6.99 (5, 1 H), 6.74 (y, 135-825 93.16 Hz, 1 H), 5.11 (a, U-18.95 567 ,2 o Hz, 2 N), 4.33 (a, 9-18.57 Hz, 1

H), 2.99 - 3.04 (t, 1 H), 2.85 - (5-(1-trifluoromethyl-cyclopropyl)- 2.92 (t, 1 H), 2.03-2.12 ( t, 1 isoxazole-Z-ylI-amide 5-((5)-7-H), 1.50 - 1.59 (t, 4 H), 1.20 (a, cyclopropane-carbonyl-b-methyl- 5,6,7,8- /|)-6.82 Hz, C H), 0.78 - 0.89 (t, tetrahydropyridoiZ,4-4|pyrimidine-4-4)yloxy)-indole-1- carboxylic acid (DMSO-dv) 6 ppm 11.27 (5,

M y; 1 H), 8.52 (Bu. 5.), 8.50 (5), 8.29 and dx (a, 9-91 Hz, 1 H), 8.17 (a, 9U-3.5

M. 22 M i iv) Hz, 1 H), 7.47 (a, 9-2.5 Hz, 1 H), rya M 7.15 (da, U-8.8, 2.5 Hz, 1 H), pi, o nn 6.76 (9, 9-3.8 Hz, 1 H), 6.68 (5, 1 135-852 A. H), 5.16 - 5.24 (t), 5.13 (4, 489,

Ge) y-19.5 Hz), 4.70 - 4.82 (t), 4.47 (B-tert-butylisoxazol-3-yl)-amide 5-((5)- | 7 7564 (tu, 4.05 (y, U-19.7 Hu), 7-acetyl-b-methyl-5,6,7,8- 3.02 - 8.16 (t), 2.77 - 2.89 (t ), tetrahydropyrido3,4-a|pyrimidine-4-2.17 (8), 2,12 (5), 1,34 (5), 1,21 yloxy)-indole-1-carboxylic acid (a, 5-66 Hz ), 1.07 (9.9-6.8 Gu) (DMSO-dv) 6 ppm 11.26 (5, about 1 H), 8.52 (Bu. 5.), 8.50 ( 5), 8.29 g X (a, 9-8.8 Hz, 1 H), 8.17 (a, 9U-3.8 so Hz, 1 H), 7.47 (a, 9-2, 3 Hz, 1 N),

М M «di 7.15 (da, U-9.0,2.4 Hz, 1 H), , ой 6.76 (y, 9-3.8 Hz, 1 H), 6.70 (5, 1

MO 7 H NU, 5.16 - 5.22 (t), 5.13 (d, 1535-77 A. 219.7 Hz), 4.76 (4, 18.7 gi), 00007 (in) 4 .56 - 4.64 (t), 4.43 - 4.55 (t), (5-isopropylisoxazol-3-yl)-amide 5-((5)-7- | 4.05 (a, uU- 20.0 Hz), 3.03 - 3.17 acetyl-b-methyl-5,6,7,8- (t,2 H), 2.77 -2.87 (t), 2.17 tetrahydropyridoi3, 4-a|pyrimidine-4- (5), 2.12 (5), 1.29 (a, U-6.8 Hz, 6 yloxy)-indole-1-carboxylic acid NU, 1.21 (a, 9-68 Hz), 1.07 (y, 3-6.8 Hz) (DMSO-dv) 6 parts/million 11.19 "still; (Bg. 5., 1 H), 8.49 (in , 1 H), 8.29 i z xx (a, 9-8.8 Hz, 1 H), 8.15 (y, 9U-3.8

M. z M 7o Hz, 1 N), 7.45 (a, 9-2.3 Hz, 1 N), in s TI 7.13 (aa, U-9.0, 2.4 Hz, 1 N ), with M 6.74 (9, 9-3.5 Hz, 1 H), 6.65 (5, 1 1850 Mo" on H), 5.18 (bg. v.), 5.14 (d , 9-19.5 5132

Hz), 4.59 (a, U-18.7 Hz), 4.33 - ' 73 4.50 (t), 4.06 (a, 9U-19.5 Hz), 3.40 - 3, 59 (t, 1 H), 2.92 - 3.04 (5-cyclopropylisoxazol-3-yl)-amide 5- (t), 2.71 - 2.90 (t), 2.04 - 2.36 ((5)-7-cyclobutane-carbonyl-b6-methyl- (t), 1.86 - 2.02 (t), 1.67 - 1.83 5,6,7,8-tetrahydropyrido!|Z, 4-4|pyrimidine- | (t, 1 H), 1.18 (a, 9-6.8 Hz), 1.01 4-yloxy)-indole-1-carboxylic acid -1.11 (t), 0.89 - 0.98 (t)

(DMSO-dv) 6 ppm 10.38 (5, 1 N), 8.52 (Bg. 5.), 8.50 (5), 8.27

Mo); x (a, 9-91 Hz, 1 H), 8.12 (a, 9U-3.5 t IF; Hz, 1 H), 8.10 (5, 1 H), 7.97 (j,

M. 22 M U-10.1 Gu, 1 N), 7.65 (imaginary i, p Sz o y-8.0 Hz, 1 N), 7.48 - 7.54 (t, 1 ke o nn H), 7.43 - 7.52 (t, 2 H), 7.15 135-Ma p (aa, 9U-8.8, 2.3 Hz, 1 H), 6.80 (a, 510, 1 o) 93.5 Hz, 1 N), 5.17 - 5.23 (t),

3-trifluoromethylphenyl)-amide 5-((5)-7- 12513 (0, U-18.7 Hz), 4.69 - 4.81 cm in netyl uv. (9) (t), 4.43 - 4.65 (t), 4.05 (y, tetrahydropyridoyi3,4-a|pyrimidine-4-4-19.5 Hu), 3.02 - 3.14 (t), 2.78 yloxy)-indol- 1-carboxylic acid -2.89 (t), 2.17 (rg. 5.), 2.12 (Big. 5.), 1.21 (a, 9U-6.6 Hz), 1.08 ( a, 3-6.8 Hz) (DMSO-dv) 6 ppm 11.22 (5, 1 N), 8.52 (bg. 5), 8.50 (c), 8.28

We are from (9, 94-91 Hz, 1 H), 8.16 (a, 9-3.8 hundredth Hz, 1 H), 7.47 (a, 9-2.3 Hz, 1 H),

M M - 7.15 (yes, U-9.0,2.4 Hz, 1 N), р M 6.76 (9, 9-3.5 Hz, 1 N), 6.65 (5, 1

Me o nn H), 5.24 - 5.30 (t), 5.20 (y, 135-Mu/a at-19.5 Hz), 4.85 - 4.98 (t), 4.70 515.3 (in) - 4.84 (t), 4.52 (j, U-16.4 Gu), 4.07 (9.9-18.7 Hz), 2.98 - 3.10 ( B-cyclopropylisoxazol-3-yl)-amide 5-((5)-p, I also (t, sl) Te b-methyl-7-((5)-2-methylbutyryl)-5,6,7,8 - 1 46 (t). 122 (a d-6 in Gu), 1.01 tetrahydropyridoyiZ,4-4|pyrimidine-4- that 13 (t) o 9 Sh o 99 (t) o 87 yloxy|-indole-1- carboxylic acid (. det gi), 0.73-0.83 t (DMSO-dv) 6 parts/million 10.63 (5.1 N), 8.52 (bg. 5.), 8.49 ( 5), 8.30 more) (a, 9-91 Hz, 1 N), 8.16 (a, 9U-3.5

Tj t If; dd Hz, 1 N), 7.44 (a, 9-2.5 Hz, 1 N),

Mi 22 M M 7.11 (aa, U-9.0,2.4 Hz, 1 H), rya M 6.71 (a, 9-3.8 Hz, 1 H), 6.40 (5, 1

M» o NN H), 5.16 - 5.23 (t), 5.12 (y, 135-X2 A. y-19.7 Hu), 4.76 (y, 9-17.4 Hu) , 5141 o 4.55 - 4.64 (t), 4.43 - 4.55 (t), 4.04 (y, 9-19.7 Hz), 3.96 (I, 9-62 (4 ,4dimethyl-Yab,5,6,7/ 0 |hc,2 H), 3.00 - 3.14 (t), 2.75 - tetrahydropyrazolo|1,5-a|pyridin-2-yl)- 2 .87 (t), 2.17 (c), 2.12 (5), 1.96- amide 5-((5)-7-acetyl-b-methyl-5,6,7,8- 2 06 (t o n) 1 in 14 72 (t. 2 tetrahydropyridoyiZ,4-4|pyrimidine-4-B) 4 30 (in bn) 1 24 (a-68 yloxy)-indole-1-carboxylic acid gz) 1 07 (a ev in gu) shi (DMSO-dv) 6 parts/million 10.63 (5, o 1 N), 8.52 (B. 5.), 8.49 (5), 8.28 ha IF ; (a, 9-91 Hz, 1 N), 8.15 (a, 9U-3.5

M. is M and M Hz, 1 N), 7.44 (a, 9-2.5 Hz, 1 N), az 7.11 (aa, U-9.0,2.4 Hz, 1 N) , me o 6.71 (a, 9-3.8 Hz, 1 H), 6.28 (5, 1 ! H), 5.15 - 5.24 (t), 5.12 (a, 1357 A . 219.7 Hz), 4.76 (4, 9218.9 Hz), 000 o 4.55 - 4.62 (t), 4.46 - 4.56 (t), (4,4-dimethyl- 5,6b-dihydro-4H-pyrrolo|1,2- | 4.09 (i, 9-6.9 Hz, 2 H), 3.04 -

Bipyrazol-2-yl)-amide 5-((5)-7-acetyl-b-|3.14 (t), 2.77 - 2.89 (t), 2.34 (i, methyl-5, 6,7,8-tetrahydropyridoiZ,4-Y-6,8 Hz, 2 H), 2,17 (5), 2,12 (5), a)pyrimidin-4-yloxy)-indole-1-carboxylic acid| 1.32 (5, 6 H), 1.21 (4, 9U-6.8 Hu), acids 1.07 (a, 9-6.8 Hz)

He) (DMSO-dv) 6 ppm 10.63 (5, o If; and 1 N), 8.51 (5, 1 N), 8.28 (a, 9-94

M. 22 M no M Gu, 1 H), 8.15 (a, 9-35 Hz, 1 H), rya M 7.45 (a, 9-2.5 Hz, 1 H), 7.12 ( aa, mon prio Nv

Ц, з, З, 77, т 135 о 5.27 (t), 4.42 - 4.73 (t), 4.09 526.2 (imaginary и, У)-6.9 Hz, 2 H) , 2.99 - (4,4-dimethyl-5,6-dihydro-4H-pyrrolo|1,2- 317 (t), 2.76 - 2.95 (t), 228 - : : : 2.39 (t ), 2.07 - 2.21 (t), 1.24

B|pyrazol-2-yl)-amide 5-((5)-7- (og. 8.), 1.03 --1.15 (t), 0.81 - cyclopropanecarbonyl-b-methyl-5, 6,7,8- And what is tetrahydro-pyridoIZ,4-4|pyrimidine-4- 0.91 (t), 0.70 - 0.81 (t) yloxy)-indole-1-carboxylic acid (DMSO- dv) 6 parts/million 10.71 (5, 1 N), 8.42 - 8.59 (t, 1 N), 8.31 "DK e) (a, 9-9.09 Hz, 1 N ), 8.21 (a,

Ty m: x r. X 9-3.54 Hz, 1 N), 7.78 (0.9-2.27

M. Z. M. Rai; Hu, 1 H), 7.44 (a, 90-227 Hz, 1 H), ra M 7.11 (da, y-8.97,2.40 Hz, 1 H), o, M 6.70 (a, 9-3.54 Hz, 1 N), 6.52 (y, mm" on 9-2.53 Hz, 1 N), 5.02-2.77 135-Ada A. 2 sets of signals are detected 488.1 o with a ratio of approximately (1-tert-butyl-1H-pyrazol-3-yl)-amide 5- | 3/2, total 5 H; 5.02 - 5.27 (t), (5)- 7-acetyl-b-methyl-5,6,7,8- 4.76 (a, 9-18.44 Hz), 4.43 - 4.64 tetrahydropyridoyiZ,4-4|pyrimidine-4- (t) , 4.05 (y, 9U-19.20 Hz), 3.01 - yloxy)-indole-1-carboxylic acid 3.13 (t), 2.77 - 2.91 (t) (2.17 ( 5) 2.12 (5) total Z H | 1.54 (5, 9) 11.21 (a, 9-6.57 Hz), 1.07 (a, 9-6.57 Hz) total Z NO o (DMSO-dv) 6 ppm 12.13 ge X (Bg. 5., 1 N), 10.56 (bg. 5., 1 N), t 8.48 (5, 1 N), 8.30 (a, U-8.8 Hz, 1

M M si NI, 8.17 (a, 9-3.3 Hz, 1 H), 7.42 rya (a, 9U-2.0 Hz, 1 H), 7.09 (a, U-9, 1

M o nn Hz, 1 N), 6.71 (a, 9-35 Hz, 1 N), 135-AB 6.29 (ru. 5., 1 N), 4.63 (5.2 N), 557.3 they are 3.77 - 3.89 (t, 2 H), 2.89 - 2.96

C (t, 1 N), 2.76 - 2.83 (t, 1 N),

I, 2.64 -2.74 (t, 2 H), 2.51 - 2.61

I5-(1-methylcyclopropyl)-1H-pyrazol-3- (t, 6H), 1.41 (z, C H), 0.87 - yl|-amide 5-I7-(3-diethylaminopropionyl)- 1.01 (t, 8 H), 0.74- 0.82 (t, 2 5,6,7,8-tetrahydropyridoiZ,4-4|pyrimidine-n) 4-yloxy|-indole-1-carboxylic acid (not in ! and

M. 2 Fa u. about M

Mche, o and Complex NMR spectrum of 135-AS A due to the presence of both 514

Ge) of reversible isomers and

M diastereoisomers.

N

(5-cyclopropylisoxazol-3-yl)-amide 5-((5)-7-(azetidine-2-carbonyl)-6-methyl-5,6,7,8- tetrahydropyridoyl 3,4-4|pyrimidine-4- yloxy|-indole-1-carboxylic acid o (DMSO-dv) 6 ppm 11.20

Ma X (og. 8., 1 H), 8.50 (5, 1 H), 8.28 and o (a, 9-9.09 Hz, 1 H), 8.16 (a,

М M svi 9-3.54 Hz, 1 N), 7.46 (y, 9-2.53

Y rak Hz, 1 H), 7.15 (ai, 9U-8.97, 2.40 m" on Hz, 1 H), 6.75 (a, 9-3.54 Hz, 1 H), 6 .65 (5, 1 H), 5.18 (bg. 5., 2 H), 135-240 o 4.26 (be. 8., 1 H), 3.06 (Bk. 5., 1 a

Mn, H), 2.80 (4.9-16.93 HZ, 1 H), (5-cyclopropylisoxazol-3-yl)-amide 5-|(5)-t g mu to (pz catch 7-( 1-amino-cyclopropanecarbonyl)-6-1 14 (t 2) of them 91 that OZ (t З methyl-5,6,7,8-tetrahydropyridoyiZ,4-n) 0 81-0 90 (t 1 n) o b5 -- d|Ipyrimidin-4-yloxy|-indole-1-carboxylic acid 0.79 (t, 2 n) And that acids

M. 0 (DMSO-dv) 6 ppm 8.49 (5.1 "pe If; and H), 8.29 (a, 4-8.84 HZ, 1 H), 8.15

M. i M (o) (a, 9-3.79 Hz, 1 H), 7.45 (y,

X M 9u-2.53 Hz, 1 H), 7.13 (da, U-8.97, m» o and 2.40 Hz, 1 H), 6.74 (d, 9-3.79 Hz , 135-AE 1 H), 6.65 (5, 1 H), 4.09 - 4.32 5161 7. (t, 2 H), 2.93 - 3.13 (t, 2 H), and 2.76 (d, 9-17.18 Hz, 2 N), 2.64 -

MH, 2.69 (t, 1 H), 2.10 - 2.22 (t, 1 (B-cyclopropylisoxazol-3-yl)-amide 5-((5)- H), 1.36 (a, 9U-4.80 Hz, 6 H), 1.19 7-(2-amino-2-methylpropionyl)-b-methyl- |(a, 9-6.82 Hz, C H), 1.03 -1 ,12 5,6,7,8-tetrahydropyrido|3,4-4|pyrimidine- | (t, 2 H), 0.90 - 0.98 (t, 2 H) 4-yloxy|-indole-1- of carboxylic acid "still (DMSO-dv) 6 ppm 8.50 (5.1 x X H), 8.28 (4.9-8.8 Hz, 1 H), 8.14

M r IF; ah (a, 9-3.8 Hz, 1 H), 7.44 (y, 9-2.3 s HC, 1 H), 7.11 (49, 9U-9.0, 2.4 Hz, for 1 NU, 6.71 (a, 9-3.5 Hz, 1 H), 6.27

MO" (5.1 N), 5.06 - 5.25 (t), 4.64 - 135-AE A mn, 4.83 (t), 439--461 (t), 411-152 9) 4.15 (t), 4.09 (i, 9-6.8 Hz, 2 H), (4,4-dimethyl-5,6b-dihydro-4H-pyrrolo|1,2- | 3.37 - 3.61 (t), 2.97 - 3.14 (t), pIpyrazol-2-yl)-amide 5-((5)-7-(2- 2.84 (rg. 5.), 2, 79 (rg. 8.), 2.30 - aminoacetyl)-6-methyl-5,6,7,8- 2.38 (t, 2 H), 1.32 (5.6 H), 1.15 tetrahydropyridoyiZ,4-4|pyrimidine-4- -1.25 (t), 1.02 -1.13 (t).yloxy|-indole-1-carboxylic acid (DMSO-dv) 6 parts/million 8, 53 (5),

Mo with 8.46 (c) 8.33 (y, 94-9.09 HZ, 1 H), i.e. IF; xz 8.14 (a, 9-3.79 Gu, 1 H), 7.43 (a,

M. M 8,922.27 Hz, 1 H), 7.10 (49, 9-8.97, re M 2.40 Hz, 1 H), 6.70 (d, 9-3.54 Hz,

M cha, o NN 1 H), 6.63 (5.1 H), 5.17 (t), 5.15 135-ASA (a, 9U-19.20 Hz), 4.43 (t), 4.24 - 5141 o 4.31 (t), 4.10 (y, 9-19.45), 3.82

MH - 3.96 (t), 3.63 - 3.81 (t), 2.94 (B-cyclopropylisoxazol-3-yl)-amide 5-((5)-7 206 (t), 2.72 - 2.89 (t), 2.08 7-(azetidine-3-carbonyl)-b-methyl-5,6,7,8-| 7 2.19 (t, 1 Well, 1.18 (a, 5- 6.82 tetrahydropyridoi3,4-4|pyrimidine-4-Hz), 1.02 -1.13 (t), 0.84 - 0.96 yloxy|-indole-1-carboxylic acid (t)

ha and; (DMSO-4b) 5 ppm 10.63 (5, a 1 N), 8.51 (5, 1 N), 8.29 (a, 2-8.8

Mo M - Hz, 1 H), 8.15 (a, 9-3.8 Hz, 1 H), р M 7.44 (a, 9-2.5 Hz, 1 H), 7.12 ( yes

MO o nn 9-9.0, 2.4 Hz, 1 N), 6.71 (y, 9-33

Hz, 1 N), 6.27 (5, 1 N), 5.28 (ri. 135-AN point 8.1), 427(b85.,1 NN), 409(50032

Mn, 3-6.8 Hz, 2 N), 2.95 - 3.12 (t, 1

I I NU, 2.81 (a, U-16.7 Hz, 1 H), 2.27 (4,4-dimethyl-5,b-dihydro-4H-pyrrolo/1,2- |. 2.37 (t, 2 H), 1.50 (bg. 5., 6 H),

BIpyrazol-2-yl)-amide 5-(5)-7-(2-amino-2- 1,32 (5, 6 H), 1,22 (a, 9-66 Hz, C methyl-propionyl)- 6-methyl-5,6,7,8-n) tetrahydropyrido|3,4-4|pyrimidin-4-yloxy|I-indole-1-carboxylic acid (DMSO-dv) 6 parts/million 10.56 ( 5, 1 H), 8.52 (B. 5.), 8.50 (5), 8.30 "more (a, 9-8.8 Hz, 1 H), 8.17 (a, 9U- 3.3

C Xe xx Hz, 1 N), 7.44 (a, 9-2.5 Hz, 1 N),

M. Zh M U SMN 7.11 (aa, 20-91.2.3 Hz, 1 H),

H. TI 6.70 (a, 9-3.8 Hz, 1 H), 6.29 (5.1 o MN H), 5.16 - 5.25 (t), 5.12 (y, 135 -Aa M I o n U-19.7 Hz), 4.76 (a, U-18.7 Gu), 486.2

A. 4.55 - 4.63 (t), 4.48 - 4.54 (t), iv) 4.04 (a, 9U-19.5 Hz), 3.03 - 3.15

15-(1-methylcyclopropyl)-1H-pyrazol-3- (t), 2.74-2.88 (t), 2.17 (5), yl|-amide 5-((5)-7- Acetyl-b-methyl-5,6,7,8- 1212 (5), 1.41 (5, C H), 1.21 (9, tetrahydropyridoi33,4-4|pyrimidine-4-U-6,6 Hz), 1.07 (y, 9-68 Hz), yloxy)-indole-1-carboxylic acid 0.89 - 0.97 (t, 2 H), 0.74 - 0.80 t, 2 H

We with (DMSO-dbv) b freq./million 10.60 (5, ty If; dx 1 N), 8.50 - 8.55 (t), 8.49 (v),

M. M and M 8.29 (a, 9U-9.0 Hz, 1 H), 8.16 (a, rya M 93.5 Hz, 1 H), 7.44 (y, 9-2.4 Hz,

Me o nn 1 H), 7.11 (aa, 9-9.0, 2.4 Hz, 1 135-ASH2 A. NO, 6.71 (a, 9-3.7 Hz, 1 H), 6 .28 4722 o (5.1 H), 5.06 - 5.23 (t), 4.70 - (5,b-dihydro-AN-pyrrolo|1,2-b|pyrazole-2- | 782 ( t), 4.40 - 4.66 (t), 9.94. - yl)-amide 5-((5)-7-acetyl-b-methyl-5,6,7,8-711 (t) , 3.03 - 3.14 (t), 2.78 - tetrahydropyridoi3,4-4|pyrimidine-4- 2.91 (t), 2.17 (5), 212 (5), 1.21 yloxy) -indole-1-carboxylic acid (9, 9-6, Hz), 1.00 - 1.10 (t)

Mao x Due to the presence of IF; two reversible isomers relatively

M. 2 M and the amide bond, the H NMR spectrum, and the M line taken at 27 "С, is complex and

Me (c) H only some signals are given

NMR. (DMSO- av) 6 parts/million 135-AKa F) 11.22 (5, 1 H), 8.51 (5, 1 H), 8.28 555.3 (a, 9-91 Hz, 1 H), 8.16 (a, U-3.8

Hz, 1 H), 7.47 (a, 9-2.3 Hz, 1 H), (B-cyclopropylisoxazol-3-yl)-amide 5-((8)- 7:15 (ai, 959.0 , 2.4 Hz, 1 H), b-methyl-7-(2,2,3,3- 6.76 (9, 9-3.3 Hz, 1 H), 6.65 (5, 1 tetramethylcyclopropane -carbonyl)- H), 211-225 (t, 1 H), 1.20 (5, 5,6,7,8-tetrahydropyridoyiZ,4-4|pyrimidine- 6 H), 1.19 (5, 6 H) 4-yloxy|-indole-1-carboxylic acid

(DMSO-dv) 6 ppm 11.23 (5,

M y; 1 H), 8.52 (bBg. 5.), 8.50 (5), 8.28 and dl (a, 9-8.8 Hz, 1 H), 8.16 (a, 9U-3, 8

M. 22 M ge Hz, 1 N), 7.47 (a, 9-2.3 Hz, 1 N), rya M 7.15 (da, U-9.0,2.4 Hz, 1 N) , me o nn 6.76 (a, 9-3.8 Hz, 1 H), 6.71 (5, 1 135-Ag a A H), 5.17 - 5.25 (t), 5.06 - 5.17 447.0

Ge) (t), 4.76 (a, U-18.9 Hz), 4.42 - (5-methylisoxazol-3-yl)-amide 5-((5)-7- | 4.64 (t ), 4.05 (y, U-19.2 Gu), acetyl-b-methyl-5,6,7,8-Z,b2 -3.16 (t), 2.73 - 2.89 (t ), tetrahydropyrido|3,4-4|Ipyrimidine-4- 2,44 (5, Z H), 2,17 (5), 2,12 (5), yloxy)-indole-1-carboxylic acid according to (a , 3-6.8 Hz), 1.07 (y, 9-68

Ts g y; ! co

Kk X-m 135-AM U-1 o nn 471.0 (c) (5-cyclopropylisoxazol-3-yl)-amide 5-(6-cyclopropanecarbonyl-b,7-dihydro-5H-pyrrolo|3,4- 4|pyrimidin-4-yloxy)-indole-1-carboxylic acid g and; ! co

K X-m 135-AM U o H 473.0 (c) (5-cyclopropylisoxazol-3-yl)-amide 5-(6- isobutyryl-b,7-dihydro-5H-pyrroloi|3,4- a| pyrimidine-4-yloxy)-indole-1-carboxylic acid

Mo (DMSO-dbv) b freq./million 10.27 (5, and If; E 1 H), 8.66 (and, 9U-5.56 Hz, 1 H),

Mi M 8.27 (aa, U-8.84, 2.78 Hz, 1 H), 8.10 (a, 9U-3.79 Hz, 1 H), 7.92 -

M ob E HE 8.05 (t, 1 N), 7.69 (i, U-6.82 Hz, 135-AO )- 1 N), 7.46 - 7.55 (t, 1 N), 7.16 500.9 (c) (aa, 9y-4.80, 2.27 Hz, 1 H), 7.18 (2-fluoro-3-trifluoromethylphenyl)-amide 5- | (aa, Y-4.80, 2.53 Hz, 1 H), 6.82 (6-acetyl-6,7-dihydro-5H-pyrrolo|3,4- (a, 9-1.26 Hz, 1 H), 4.97 (5.1 H), α|pyrimidin-4-yloxy)-indole-1-carboxylic acid | 4.90 (5, 1 H), 4.63 (y, U-3.79 Hu, acids 2 NN), 2.11 (a, U-6.57 Hz, C H) (DMSO-dv) 6 frequency/million 11.13 (Bg. 5., 1 H), 8.59 (y, 9-5.05 Hz, 1

Ma o X H), 8.22 (a, 9-2.02 Hz, 1 H), 8.10 (y o (a, 9-3.54 Hz, 1 H), 7.42 (Bu. 5 ., 1

M M z-d H)U, 7.10 (id, 2-4.29,2.78 HC, 1 135-AR M re H), 6.69 (brg. 5., 1 H), 6, 58 (5, 1 445.9 - o nn H), 4.90 (5, 1 H), 4.83 (5, 1 H), 4.56 (rg. 5., 2 H) 2.04 ( y, 9U-5.81 o Hz, C H)2.01-2.14 (t, 1 H), (5-cyclopropylisoxazol-3-yl)-amide 5-(6-|1.02 (ad, 9U-8.34,2.27 Hz, 2 H), acetyl-b, 7-dihydro-5H-pyrrolo|3,4- 0.87 (aa, 9U-4.55, 2.27 Hz, 2 H )

Nini INNA PI acids

M. 0 (DMSO-av) b frequent./million 11.26 more If; d (rg. 5., 1 H), 8.66 (a, 9-5.05 Hz, 1

M. M o; H), 8.31 (yes, U-9.09, 2.53 Hz, 1

Khm H), 8.18 (a, 9-3.79 Hz, 1 H), 7.50

M on (9.94-2.78 Hz, 1 H), 7.15-7.23 135-AO - (t, 1 H), 6.77 (a, 922.53 Hz, 1 447.9 ( c) H), 6.69 (5.1 H), 4.97 (5.1 H), (B-isopropylisoxazol-3-yl)-amide 5-(6- 4.90 (5.1 H) , 4.64 (5.2 N), 3710 acetyl-b,7-dihydro-5H-pyrrolo|3,4-(a, 9-7.33 Hz, 1 N), 2.11 (a, a| pyrimidine-4-yloxy)-indole-1-carboxylic acid | 9U-6.32 Hz, C H), 1.29 (y, 9U-7.07 Hz acid, in H) (DMSO-dv) 6 parts/ million 11.28 (5, "more; 1 N), 8.66 (9, U-7.07 Hz, 1 N), ee IF; and 8.31 - 8.33 (t, 1N), 8, 18 (4,

M. M 8 u-4.04 Hz, 1 N), 7.50 (i, 922.27 and M Hz, 1 N), 7.16 - 7.20 (t, 1 N), o 6.79 (a, 9-1.77 HZ, 1 N), 6.70 (5, 135-AN 4 and 1 N), 5.03 (5, 1 N), 4.95 (4, 415.9 (in ) 9-1.26 Hu, 1 H), 4.65 (5.2 H), (B-isopropylisoxazol-3-yl)-amide 5-(6- 3.08 -3.15 (t, 1 H ), 2.79 -2.85 isobutyryl-6,7-dihydro-5H-pyrrolo|3,4-|(t, 1 H), 1.29 (a, U-6.82 Gu, 6 a|pyrimidine -4-yloxy)-indole-1-carboxylic acid|H), 1.09 (a, 9U-5.31 Hu, 2 H), 1.08 acid (a, 9U-5.56 Hz, 4 H) ( DMSO-dv) 6 parts/million 11.25

Mao x (rg. 5., 1 H), 8.66 (a, 9-4.80 Hz, 1 (y Kho H), 8.24 - 8.42 (t, 1 H), 8.17 ( 4,

M MO -k Ch-3.54 Hz, 1 H), 7.49 (y, 9-3.28

M rya Hz, 1 N), 7.17 (9, 4-6.06 Hz, 1 N), 135-A5 u- o nn 6.77 (Bg. 5., 1 N), 6.67 (5 , 1 MN), 459.9 4.97 (5, 1 N), 4.90 (bg. 5., 1 N), c) 4.64 (bg. 8., 2 N), 2.10 - 2.11 (t, (5-(1-methylcyclopropyl)-isoxazol-Z-yl|- | Z H), 1.46 (5, Z H), 1.15 (4, amide 5-(6-acetyl -6,7-dihydro-5|H- 92.27 Hz, 2 H), 0.93 (y, 9-2.53 pyrrolo|3,4-a|pyrimidin-4-yloxy)-indole-1- | Hz, 2 N) carboxylic acid (DMSO-dv) 6 ppm 11.25 (5, about 1 N), 8.66 (4, U-8.34 HZ, 1 N),

Ma X 8.28 - 8.31 (t, 1 H), 8.18 (a, i sa Ch-3.79 Hz, 1 H), 7.50 (y, 9-2.27

M M di hz, 1 Well), 7.17 -7.18 (t, 1 H),

Measured 6.78 (a, 9-3.28 HZ, 1 H), 6.67 (5, 135-AT y-4 o n 1H), 515(5.1H), 5.07(5.1H ), | 485.9 4.67 (Bg. 5., 2 H), 1.92 - 1.99 (t, o 1H), 1.46 (5, C H), 1.16 (ad, 9-2, 53 (5-(1-methylcyclopropyl)-isoxazol-3-yl|- | Hz, 2 H), 1.16 (a, 9-10.86 Hz, 1 amide 5-(6b-cyclopropanecarbonyl-b,7- H), 0.94 (4, 922.27 Hz, 1 H), 0.89 dihydro-5H-pyrrolo|3,4-soIpyrimidine-4- /|-- 0.99 (t, 1 H), 0 .83 (a, Y-3.03 yloxy)-indole-1-carboxylic acid Hz, 1 H), 0.83 (a, 9-8.84 Hz, 2 H)

(DMSO-dv) 6 ppm 11.25 (5,

Ma o X 1 H), 8.66 (a, 9U-7.07 Hz, 1 H), and so 8.30 - 8.931 (t, 1 H), 8.18 (y,

M M z-d 93.79 Hz, 1 N), 7.41 - 7.59 (t,

K Khm 1 n), 710-729 (t, 1 N), 6.79 135-A and o nn (a, 9-2.02 Hz, 1 N), 6.67 (5.1 N), 487 .9 5.03 (5, 1 H), 4.96 (5, 1 H), 4.65 o (5, 2 H), 2.84 (yes, 9U-16.17, 6.82

15-(1-methylcyclopropyl)-isoxazole-3-yl|- | Hz, 1 H), 1.46 (5, C H), 1.15 - amide 5-(6-isobutyryl-b,7-dihydro-5H- 1.17 (t, 2 H), 1.07 - 110 (t, pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1- | 6H), 0.93 - 0.95 (t, 2 H) carboxylic acid

M. 0 (DMSO-dv) 6 parts/million 11.19 "me If; and (Bg. 5., 1 H), 8.59 (4. 4-5.05 HZ, 1

M. 2 M What |in; H), 8.23 - 8.25 (t, 1 H), 8.11 (y, p M 93.79 Hz, 1 H), 7.43 (Bg. 5., 1 H),

M 7.43 (a, 9-5.56 Hz, 1 N), 7.08 - 135-AU - on 78 (t, 1 N), 6.70 (6.5.1), 1007919 o 6.71 ( 9, 9-1.52 Hz, 1 H), 6.61 (5, (B-tert-butylisoxazol-3-yl)-amide 5-(6-12 NI), 4.90 (5, 2 H) . α|pyrimidin-4-yloxy)-indole-1-carboxylic acid 5 H) 1.28 (5, ЗН) acid

IS

M. 0 (DMSO-dv) 6 ppm 11.45 (5,

And in If; dec and 1 N), 8.66 (y, 9U-8.34 Hz, 1 N),

М. Ж M щ |c) 8.31 (aa, 9U-9.09, 3.03 Hz, 1 H), r M 8.18 (а, 9-3.79 Hz, 1 H), 7, 51 (a,

M o them y-2.53 Hz, 1 N), 7.19 (ai, 9U-8.97, 135-AMU U-1 2.40 Hz, 1 N), 7.04 (5, 1 N) , 6.79 539.9 o (i, 9-3.28 Hz, 1 H), 5.15 (5.1 H), (5-(1-trifluoromethyl-cyclopropyl)- 5.07 (5, 1 NU, 4.66 (y, 9-3.28 Hz, isoxazol-3-ylI-amide 5-(6-2 H), 1.80-210 (t, 1 H), 1.44 - cyclopropanecarbonyl-6,7 -dihydro-5H- 1270 (t, 4 H) 0.71 - 0.95 (t, 4 pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-H) carboxylic acid

IS

(DMSO-dv) 6 ppm 11.46 (5,

Mach o X EE 1 H), 8.66 (a, U-6.82 Hz, 1 H), (y me 8.31 (aa, U-8.97, 1.89 Hz, 1 H),

M M s 8.18 (a, 9-3.79 Hz, 1 H), 7.50 (i,

M re 9U-52.27 Hz, 1 H), 7.19 (ai, 9U-9.09, 135-AH and o nn 2.27 Hz, 1 H), 7.05 (5, 1 H), 6.79 541.9 (aa, 9U-3.28, 1.77 Hz, 1 H), 5.03 o (in, 1 H), 4.95 (in, 1 H), 4.65 (a ,

I5-(1-trifluoromethyl-cyclopropyl)-3-6.32 Hz, 2 H), 2.75-2.92 (t, isoxazol-3-yl|-amide 5-(6-isobutyryl-b, 7- |1 H), 1.46 - 1.68 (t, 4 H), 1.01 - dihydro-5H-pyrrolo|3,4-4|pyrimidine-4- 1.22 (t, 6 H) yloxy) -indole-1-carboxylic acid o (DMSO-dv) 6 ppm 11.24 (5, g X 1 H), 8.66 (y, 9U-5.05 Hz, 1 H), i 8, 30 (a, 9-8.84 Hz, 1 N), 8.31 (a,

M M z-d 9-9.09 Hz, 1 N), 8.18 (a, U-3.79 135-AU M Xm Hz, 1 N), 7.50 (a, 95.81 Hz, 1 NN), 4191 u- o nn 7.16 - 7.20 (t, 1 N), 6.78 (y, 95.56 Hz, 1 N), 6.71 (a, 9-1.26 o HC , 1 H), 4.97 (5, 1 H), 4.90 (5, 1 (5-methylisoxazol-3-yl)-amide 5-(6-NU, 4.64 (y, 9-1, 52 Hz. 1-carboxylic acid (DMSO-dv) parts/million 11.28 (5.1 "still H), 8.49 (B. 5.), 8.46 (rg. 5.), 8.13

Yes with xx - 8517 (t) 8.12 (Be. 5.), 7.10 (a,

M. is M 7 (o, y-8.84 Hz, 1 N), 6.88 (y, 9-3.79

M Hz, 1 N), 6.70 (in, 1 N), 5.20 (rg.

M sa ob 5.), 5.16 (Brg. 5.), 5.11 (Bg. 5.), 4.80

Y (Bg. 5.), 4.75 (rg. 5.), 4.57 - 4.63 135-Aza A (t), 4.55 (og. 5.), 4.50 (bg. 8 .), 489.2 o) 4.05 (y, 9-19.45 Hz, 1 H), 3.05 - (5-isopropylisoxazol-3-yl)-amide 5-((5)-7- | 3.18 (t), 2.82 - 2.91 (t), 2.21 (in, acetyl-6-methyl-5,6, 7,8- Z H), 2.18 (5.2 NN ), 2,13(5,1 H), tetrahydropyridoyi3,4-4|pyrimidine-4- 1,29 (a, 2-7,07 Hz, 6 H) 1,21 (a, yloxy)-4-methylindole -1-carboxylic acid 9-6.82 Hz, 2 N), 1.08 (a, 9-6.82 Hz acid, 1 n) (DMSO-dv) parts/million 11.25 (5, 1

H), 8.49 (B. 5.), 8.46 (rg. 5.), 8.13

He) - 8.16 (t), 8.12 (5.1 N), 7.10 (a,

Ti t Z de 9-9.09 Hz, 1 N), 6.87 (y, 9-3.79

M. 2 M io) HC, 1 H), 6.68 (5.1 H), 5.17 - rya M 5.24 (t), 5.16 (Brg. v5.), 5.11 (Bg .

Me o nn 5.), 4.80 (rg. 5.), 4.75 (Bg. 5.), 4.56 135-VA? AH - 4.64 (t), 4.54 (ru. 5.), 4.50 (rg. 501.2 o 5.), 4.08 (rg. 5.), 4.03 (Bg. 5 .), 3.13

B-(1-methylcyclopropyl)-isoxazol-3-yl|- | 3.18 (t), 3.07 - 3.13 (t), 2.85 amide 5-(5)-7-acetyl-b-methyl-5,6,7,8- -291 (t), 2.84 (g. 5.), 2.21 (5. With tetrahydropyridoiIZ,4-4|pyrimidine-4-t vva ots pu pokoy i methylindole-1-carbonov 118 (t, 2 NU, 1.08 (4 , 4-6.82 Hz, 1N),0.91-0.97 (t, 2 N

M. 0 SE (DMSO-dv) parts/million 11.45 (5.1 "Me If; AHz H), 8.66 (a, 4-5.05 HZ, 1 H), 8.31

M. z M sh |v) (aa, y-8.97, 2.15 Hz, 1 N), 8.17

X M (a, 9-3.79 Hz, 1 H), 7.51 (i, 135-BB M o! and y-2.91 Hz, 1 H), 7.19 (daa, BiZ1 - 98, 97, 4.55, 2.40 Hz, 1 N), 7.04'

He) (5, 1 H), 6.79 (da, U-4.04, 1.52

I5-(1-trifluoromethyl-cyclopropyl)-Hz, 1 NU, 4.97 (5, 1 NU, 4.90 (5, 1 isoxazol-3-yl|-amide 5-(6b-acetyl-b, 7- NU, 4.64 (5.2 H), 211 (0.9U-6.57 dihydro-5H-pyrrolo|3,4-a|pyrimidine-4- Hz, 3 H), 1.54 - 1.60 (t, 4 H) yloxy)-indole-1-carboxylic acid (DMSO-dv) parts/million 11.42 (5.1 "still; H), 8.48 (Bg. 5.), 8.46 (rg. 5.), 8.13 and s x SE. - 8.16 (t), 8.12 (Bg. 5.), 7.10 (j,

M u mo bo 9-8.84 Hz, 1 N), 7.04 (5, 1 N), with 6.88 (a, 9-3.79 Hz, 1 N), 5.17 -

M s, both 5.23 (t), 5.16 (Brg. v5.), 5.11 (Bg.

Y 5.), 4.80 (Bg. 5.), 4.75 (Bg. 5.), 4.57 135-vS AH - 4.64 (t), 4.54 (ri. 8.), 4.50 (6.100029 o 5.), 4.07 (rg. v.), 4.02 (bg. 5.), 3.15

I5-(1-trifluoromethyl-cyclopropyl)-(Bg. 5.), 3.12 (t), 2.82 - 2.91 (t), isoxazol-3-yl|I-amide 5-((5) -7-acetyl-b- 2,21 (5,1 H), 2,17 (5,1 H), 2,12 methyl-5,6,7,8-tetrahydropyridoyi3,4- (5,1 H) . (a, carboxylic acid y7.33 Hu, 1 H)

pe; (DMSO-dv) freq./million 11.23 (Bg. y y VK d 5., 1 N), 8.62 (a, 9U-6.06 Hz, 1 N),

M. and M Io; 8.03 - 8.25 (t, 2 H), 7.12 (yes, uk M 98.97, 6.19 Hz, 1 H), 6.88 (y,

M 9EZ,79 HZ, 1 H), 6.67 (5.1 H), 135-VO - on 4.82 - 5.09 (t, 2 H), 4.64 (5.2 473.2 o H), 2.26 (y, 9-4.04 Hz, C H), 2.11 (5-(1-methylcyclopropyl)-isoxazol-3-yl|- | (9, 958.59 Hz, C NU , 1.46 (5, C H), amide 5-(6-acetyl-6,7-dihydro-5H- 1.08 -1.24 (t,2 H), 0.87 - 1.01 pyrrolo| 3,4-a|pyrimidin-4-yloxy)-4- (t.2 H) methylindole-1-carboxylic acid (DMSO-dv) parts/million 11.24 (5, 1

M.,O H), 8.48 (rg. 5.), 8.46 (bBg. 5.), 8.12 pe U 2 -8.17 (t), 811 (5, 1 H), 7 .09 (4,

E. 2 M no o 98.84 Hu, 1 H), 6.87 (y, 9-3.79 re M HC, 1 H), 6.66 (5, 1 H), 5.16 -

Me o nn 5.24 (t), 5.15 (r. 5.), 5.11 (Bri. 135-VE: AH 5.), 4.80 (Bg. 5.), 4.75 (b . 3.99 - 4.10 (t), 3.16 (Bg. 5.), 3.12 ((5)-7-acetyl-b-methyl-5,6,7,8- and 5 schi pe ut Z H ), about 9 tetrahydropyridoiIZ,4-4|pyrimidine-4-shin and 2 Nu 105 (in; t B yloxy)-4-methylindole-1-carboxylic acid H),0.92-0.97 (t, 2 N) ke (DMSO-dv) parts/million 11.44 (5, 1

M M s H), 8.62 (y, 9U-6.06 Hz, 1 H), 8.04

K oi -8.26 (t, 2 H), 7.12 (ai, 9-8.84,

H 5.81 Hz, 1 H), 7.04 (5, 1 H), 6.90 135-BE )- (4.939 Hz), 484-5.07.| 2272 o (t, 2 H), 4.64 (5, 2 H), 2.26 (4, (5-(1-trifluoromethyl-cyclopropyl)-4-3.79 Hz, C H), 2.11 (a, 9-8.59 isoxazol-Z3-yl|-amide 5-(6-acetyl-b, 7- Hz, C H), 1.44 - 1.63 (t, 4 H) dihydro-5H- pyrrolo|3,4-d|pyrimidin-4-yloxy)-4-methylindole-1-carboxylic acid (DMSO-dv) parts/million 11.22 (5, 1

Tj 7 ВХ and H), 8.62 (y, 9U-6.06 Hz, 1 H), 8.02

М. Hz,

M 1 H), 6.65 (5, 1 H), 4.84 - 5.08 135-vO - o nH (t, 2 H), 4.64 (5, 2 H), 2.26 (4 . 928.59 Hz, C H), acetyl-b,7-dihydro-5H-pyrroloyi3,4- 1.06 -1.12(t,2 H), 0.92 -0.97 9|Ipyrimidine-4- yloxy)-4-methylindole-1-(t.2 H) carboxylic acid

(DMSO-dv) 6 parts/million 11.22 (5, another 1 H), 8.50 (bg. 5., 1 H), 8.28 (a, che IF; and 9-9.6 Hz , 1 H), 8.15 (a, 9-3.8 Hu,

Y m (v, 1 NU, 7.46 (y, 9-2.5 Hz, 1 N), 7.14 uj; (da, 9-9.0, 2.5 Hz, 1 N), 6, 75 (4, US M 9-44 HZ, 1 N), 6.65 (5, 1 N), 5.07 13B-VNa M o nN - 5.30 (t, 0 N), 4.78 (9 , 9-22 4v7

Gu, 0 N), 4.64 (bg. 5., 0 N), 4.49 ' 97 (a, 9-18.9 Hz, 0 N), 4.06 (4, -18.6 Hz, 0 H), 2.99 - 314 (t, (5-cyclopropylisoxazol-3-yl)-amide 5- o nH), 2.78 - 2.89 (t, 0 H), 2.10 - ((5 )-6-methyl-7-propionyl-5,6,7,8- 2,25 (t,1 H), 1,16-1,26 (t,0 tetrahydropyridoyi3,4-4|pyrimidine-4- H ), 0.099 -1.12 (t, 0 H), 0.90 - yloxy)-indole-1-carboxylic acid 0.98 (t, O H (DMSO-dv) 6 ppm 11.13 m. ,o0 (Bg. 5., 1 H), 8.50 (bg. 5., 1 H), pe If; t 8.30 (a, 4-9.0 Hz, 1 H), 8.15 ( and,

M. z M (o; 923.8 Hz, 1 H), 7.45 (y, 9-2.4 Hz,

Khm sel 1 H), 7.13 (49, U-8.9, 2.3 Hz, 1 m» o H), 6.73 (4, 9-3.8 Hz, 1 H), 6.65 135-VIV at (5.1 N), 5.19-5.25 (t), 5.11 - BOI at 5.18 (t), 4.79 (a, 9U-18.6 Hz), ' 4.59 - 4.70 (t), 4.44 - 4.53 (t), 4.01 - 4.09 (t), 3.00 - 3.12 (t), (5-cyclopropylisoxazole- Z-yl)-amide 5- 2.18 -2.88 (t), 2.36 - 2.48 (t), ((5)-7-butyryl-b-methyl-5,6,7,8 - 212-221 (t, 1 H), 1.47 - 1.64 tetrahydropyridoi3,4-4|pyrimidine-4- (t, 2 NU, 1.20 (a, 9-5.6 Hz, 2 H) , yloxy)-indole-1-carboxylic acid 1.03 -1.11 (t), 0.90 - 0.97 (t) o KE (DMSO-dv) 6 ppm 11.08 (5, gai If; E 1 H), 8.48-8.55 (t, 1 H), 8.30 (4, and M 99.09 Gu, 1 H), 8.18 (a, 9-3.79

M M is still Gu, 1 NU, 7.46 (9, 9-2.27 Hz, 1 H), . o 7.13 (y, 4-9.09 HZ, 1 H), 7.06 (5, VIA MO H 1 H), 6.75 (d, U-3.79 HZ, 1 H), 135- 895 A. 5.10-- 5.12 (t), 4.74 (VG. 8.), jaws at 4.52-4.54. (t), 4.24. (y, 92-7.07 (1-ethyl-5-trifluoromethyl-1H-pyrazole-3- | Hz), 4.01-4.10 (t), 3.10 (rg. 5.), il) -amide 5-((5)-7-acetyl-b-methyl-5,6,7,8- | 2.85 (Bg. 5.), 2.11-2.18 (t), 1.42 tetrahydropyridoyiZ,4-4|pyrimidine-4- (I, 9U-7.33 Hz), 1.20 -1.22 (t), yloxy)-indole-1-carboxylic acid 1.08 -1.10 (t )

Mao x (DMSO-sv) b parts/million 10.54 (5, (and IF; - 1 N), 8.49-8.53 (t, 1 N), 8.29 (4,

M. M What 9-9.09 Hz, 1 N), 8.18 (4, 9-3.54 ran Gu, 1 NU, 7.43 (9, 9-2.53 Hz, 1 N), m » o H 7.10 (ad, U-8.97, 2.40 Hz, 1 H), 135-VKa A. 6.69 (a, 94-3.03 Hz, 1 H), 6.37( 5, |. 5021

Ge) 1 H), 5.15-5.35 (t, 1 H), 4.05- (1-tert-butyl-5-methyl-1H-pyrazol-3-yl)- | 4.58 (t, 2 H), 3.05-3.20 (t, 1 H), amide 5-(5)-7-acetyl-b6-methyl-5,6,7,8- 2,79- 2.86 (t, 1 H), 2.45 (5, 3H), tetrahydropyrido|3,4-4|Ipyrimidine-4- 212-217 (t, 3H), 1.59 (5.9 H) , yloxy)-indole-1-carboxylic acid 1.07-1.23 (t, C H) o KA (DMSO-4v) b parts/million 11.04 (5, g If; E 1 H), 8 .46 - 8.56 (t, 1 H), 8.30

I- (4, 9-8.84 Hz, 1 N), 8.17 (4,

M M zdi 923.79 Hz, 1 H), 7.46 (y, 9-2.27 135-VI a. re Hz, 1 H), 7.14 (ai, 9-9.09, 2.53 5 and 42 ma on HC, 1 H), 7.07 (5, 1 H), 6.75 (4,

A. 9-3.79 Hz, 1 H), 5.13 (t), 4.76 o (t), 4.47 - 4.62 (t), 4.06 (5), 1-methyl- 5-trifluoromethyl-1H-pyrazole-3- | 3.99 - 4.04 (t), 3.95 (5, Z H),

yl)-amide 5-((5)-7-acetyl-b-methyl-5,6,7,8- 13.11 (rg. 5.), 3.05 - 3.09 (t), 2, 85 tetrahydropyridoiZ,4-4|pyrimidine-4- (Bg. 5.), 2.17 (Bg. 5.), 2.12 (Bi. 5.), yloxy)-indole-1-carboxylic acid 1.23 -1.28 (t), 1.17 -1.23 (t), 1.10 (5 kA) and

VI and !

I d (DMSO-dv) 6 parts/million 11.21 (5,

Mi 22 M s Io; 1 H), 8.47 (5, 1 H), 8.07-8.19 (t, weight M 2 H), 7.10 (a, 9U-9.09 Hz, 1 H), on tav vov(t B ; 4.98-5.28 (t), 4.49-4, 135-VM" o (t), 402-419 (t), 312 (6.83), 0002132 2.90 (Bg. 5.), 2,22 (5, C H), 2,14- (5-cyclopropylisoxazol-3-yl)-amide 5- as (t, 95, ov (og. and ((5)-7-cyclopropane -carbonyl-6-methyl- "13 (t), 0, "98 (t), 0, 5,6,7,8-tetrahydropyridoyi3,44|pyrimidine- 0,89 (t), 0,73-0, 82 (t) 4-yloxy)-4-methylindole-1-carboxylic acid

M. ,о0 и se Са и (DMSO-ав) 6 11.21 (5.1 N), 8.46

М. a, m» o and 93.79 Hz, 1 N), 6.65 (5.1 N),

Zh 4.67-4.88 (t), 4.22-4.34 (t), 135-8Ma i.e. 4.13 (yes, U-7.07,1.26 Hz, 2 H), 517, 1

C 2.95-3.07 (t), 2.78-2.92 (t), 2.21 (5, Z H), 1.24 (I, 9-7.07 Hz, ethyl ether (5 )-4-(1-(5- With H), 1.15 (a, U-7.07 Hz, With H), cyclopropylisoxazol-3-ylcarbamoyl)-4- | 1.05-1.11 (t . - carboxylic acid ne) and c x (DMSO-α) 6 11.21 (5.1 N), 8.46

M r M ke (g. 5., 1 H), 8.03-8.21 (t, 2 H),

TI 7.09 (a, 9-8.84 Hz, 1 N), 6.86 (a, me oh 93.79 Hz, 1 N), 6.65 (5.1 N), " 5.08- 5.27 (t, 1 H), 4.80 (bg. 8.), 135-vO» 4.62 (bg. 8.), 442-453 (t) 3.99-...2012 at 4 ,14 (t) 3.05-3.18 (t) 2.88 (bg. 5.), 2.21 (c, C H), 2.14-2.19 (t) (5-cyclopropylisoxazole- Z-yl)-amide 4- 1.21 (bg. 5.), 1.01-1.12 (t) 0.91- methyl-5-((5)-6-methyl-7-propionyl-5 .6, 7.8-|0.97 (t, 2 H) of tetrahydropyridoyi3,44|pyrimidin-4-yloxy)-indole-1-carboxylic acid

EE

M. , О E (DMSO-ав) 6 11.03 (in, 1 N), 8.43- gad SI and 8.51 (t, 1 N), 8.08-8.19 (t, 2 N ),

M. M On 7.03-7.12 (t, 2 H), 6.85 (4, rya M 93.79 HZ, 1 H), 5.13 (t) 4.71- vra py, o Hn 4.82 (t), 4.59 (ru. 5.), 4.46-4.56 135-BP A. (t), 4.00-411 (t), 3.95(5.3Н) , 292

Ge) 3.07-3.18 (t), 2.81-2.92 (t), (1-methyl-5-trifluoromethyl-1H-pyrazole-3- | 221 (5, З H), 2.17 (5, 2 H), 212 yl)-amide 5-((5)-7-acetyl-b-methyl-5,6,7,8- (5, 1 NU, 1,21 (a, 9-6 ,57 Hz, 2 H), tetrahydropyridoi3,4-a|pyrimidine-4- 1,08 (a, 956,57 Hz, 1 H)yloxy)-4-methylindole-1-carbon

1 facid//////111111111Ї1111111111111111111111111111111Ї11

KE and B; to (DMSO-аv) 6 11.07 (5.1 N), 8.42-

M. M AX 8.51 (t, 1 H), 8.10-8.18 (t, 2 H), r M 7.04-7.11 (t, 2 H), 6.85 (a, ke o nn 9U-3.54 HZ, 1 H), 5.13 (t), 4.75 135-802 A. (g. 5.), 4.54 (Bug. 5.), 4.24 ( 9, 542.21

Ge) 3-7.07 Hz, 2 H), 4.05 (t), 2.81- (1-ethyl-5-trifluoromethyl-1 H-pyrazole-3- 2,3g (t), 2.21 (5 , Z H), 217 (c), yl)-amide 5-((5)-7-acetyl-b-methyl-5,6,7,8- 2,12 (5), 1,42 (i, 9-7.20 Gu, Z H), tetrahydropyrido|3,4-a|pyrimidine-4- 1.22 (t), 1.08 (t) yloxy)-4-methylindole-1-carboxylic acid and "IN NMR spectra were taken at 27 "С in a solution in DMSO-4dv. At the same temperature, the identified compounds exist as a mixture of reversible amide isomers (presumably due to inhibited rotation around the nitrogen-carbonyl bond). This does not allow for unambiguous assignment of the signal

NMR of each proton. Chemical shift assignments, spin-spin interaction constants, and the number of protons are indicated for signals related to both rotatory isomers. Chemical shifts and spin-spin interaction constants are indicated for other peaks corresponding to individual rotational isomers.

b IN NMR spectra were recorded at the temperature indicated in the table for samples in solution in DMSO-α. At the indicated temperature, the speed of rotation around the amide bond is sufficiently high, so the H NMR signals of individual rotary isomers merge into one signal, which allows assigning each signal to the proton NMR spectrum.

Example 136 136-А. (5-Cyclopropylisoxazol-3-yl)-amide 5-((5)-7-ethyl-b6-methyl-5,6,7,8-tetrahydropyridoi|3,4-a|pyrimidin-4-yloxy)-indole -1-carboxylic acid. (6) wav; And also

M. m her 9 4 U

It is obtained by a method similar to that described in example 37. MS (IER) t/2 459.2 (M-41); "H NMR (400 MHz, DMSO-av) b frequency/million 11.21 (5, 1 N), 8.42 (5, 1 N), 8.27 (y, 9-91 Hz, 1 N) , 8.15 (y, 9-3.5 Hz, 1

H), 7.44 (a, 9-23 Hz, 1 H), 7.13 (aa, U-8.8, 2.3 Hz, 1 H), 6.75 (a, 9U-3.8 Hz, 1 N), 6.65 (5, 1 N), 3.59 - 3.75 (t, 2 N), 3.05 - 3.17 (t, 1 N), 2.93 (yes, 9U-16.7, 5.3 Hz, 1 N), 2.67 - 2.77 (t, 1 N), 2.53 - 2.64 (t, 2 N), 2.11 -223 (t ,1 H), 1.04-1.12 (t, 8H), 0.91 - 0.98 (t, 2 H).

The following compounds are obtained by a similar method.

MS (ER) 000 courts 000 mem te

MAN o) g If; The same (DMSO-v8) 5 parts per million 11.45 (rg. 5.,

M. is M (o) 1 H), 8.42 (5, 1 p), 8.29 (a, U-9.0 Hz, c: Uch 1 H), 8.15 (a, 9-38 Hu, 1 H), 7.45 (a, . o 9-2.3 Hz, 1 H), 7.14 (da, 9-9.0, 2.4

MO" Hu, 1 H), 7.05 (5, 1 H), 6.76 (y, 9-3.7 136-8 C Hz, 1 H), 3.66 (5.2 8), 306 -316 ..|.2272 (t, 1 H), 2.93 (da, 9U-17.0, 4.7 Hz, 1 (5-(1-trifluoromethyl-cyclopropyl)-H), 2.65- 2.77 (t, 1 H), 2.53 - 2.63 isoxazol-3-yl|-amide 5-((5)-7-ethyl-6- (t, 2 H), 1.52 - 1 .59 (t, 5 H), 1.03 - methyl-5,6,7,8-tetrahydropyridoyl3,4- 1.12 (t, 5 H) a|pyrimidin-4-yloxy)-indole-1-carbon acid

"more; (DMSO-dv) 6 parts/million 12.12 (5.1

E c X H), 10.55 (in, 1 H), 8.42 (5, 1 H), 8.29

St t (a, 9U-8.8 Hz, 1 H), 8.16 (a, 9U-3.8 Hz,

M 1 H), 7.42 (y, 9-2.3 Hz, 1 H), 7.09 ..,, X-m (ad, 9U-9.0.24 Hz, 1 H), 6, 70 (a, 136-S x M o nn 93.8 Hz, 1 N), 6.30 (y, 9-23 Hz, 1 472.2

C H), 3.66 (5, 2 H), 3.03 - 3.19 (t, 1

H), 2.86 - 2.98 (t, 1 H), 2.65-2.78 (5-(1-methylcyclopropyl)-1H-pyrazole-3-|(t, 1 H), 2.52 - 2.65 (t, 2 H), 1.41 yl|-amide 5-((5)-7-ethyl-6-methyl-5,6,7,8-(5, C H), 1, 02-1.13 (t, 6 H), 0.89 - tetrahydro-pyrido|3,4-4|pyrimidine-4- 0.96 (t, 2 H), 0.74 - 0.81 (t, 2 N) yloxy)-indole-1-carboxylic acid

Gee)

E Ex X (DMSO-dv) 6 parts/million 11.26 (bg. 5., so 1 N), 8.42 (5, 1 N), 8.35 (a, 9U-8.8 Hz,

M M M 1 H), 8.13 (a, 9U-3.8 Hz, 1 H), 7.41 (a, .., rya y-2.3 Hz, 1 H), 7.08 (da , 9-90, 21 136-0 MO" o n Hz, 1 N), 6.67 - 6.71 (t, 1 N), 6.66 461.2

C (5, 1 H), 3.56 (5, 2 H), 2.81 - 2.87 (t, 2 H), 2.72 - 2.79 (t, 2 H), 2.58 ( ad, (5-tert-butylisoxazol-3-yl)-amide 5-((5)- ethyl-β6-methyl-5,6,7,8-7,2 ГЦ, СН). 6 parts/million 11.21 (bBg. 5., y se X 1 H), 8.41 (5.1 H), 8.27 (y, U-9.09

So Hu, 1 H), 8.15 (a, 9-3.79 Hz, 1 H), zm 7.44 (a, 9-2.27 Hz, 1 H), 7.13 (aa, . .,, X-m u-8.97, 2.40 Hz, 1 N), 6.75 (a, U-3.28 136-E MO" o n HC, 1 N), 6.65 (5 , 1 H), 3.60 - 3.81 473.1

A (t, 2 H), 3.07 - 3.25 (t, 2 H), 2.91 (aa, 9U-17.94, 2.53 Hz, 1 H), 2.09 - (5- cyclopropylisoxazol-3-yl)-amide 5-2,2A(t,1 НН), 1,11-118(t, 6 H), ((5)-7-isopropyl-6-methyl-5,6,7 ,8- 1.05-1.11 (t, C H), 1.02 (a, 9-6.06 tetrahydropyridoyi3,4-4|pyrimidine-4-Hz, C H), 0.90 - 0, 97 (t, 2 N) yloxy)-indole-1-carboxylic acid o (DMSO-dv) 6 parts/million. 10.62 (5, 1

Ma X H), 8.42 (5, 1 H), 8.29 (y, 9-91 Hz, 1 (y at H)U, 8.15 (a, 9U-3.8 Hz, 1 H) , 7.42 (and,

M M zd y-2.3 Hz, 1 H), 7.09 (ai, 9U-9.0, 2.4 .,, ohm Hz, 1 H), 6.70 (a, 9-3.5 Hz, 1 N), 6.40

MO Hn (5, 1 N), 3.96 (i, U-6.2 Hz, 2 N), 3.57 136 sh -871 (t, 2 N), 305-347 (t, 1 N),, 00 2.92 (aa, 9U-17.1, 4.7 Hz, 1 H), 2.65 - (44-dimethyl-4,5,6,7-tetrahydro- 2.78 (t, 1 H) , 2.51-265 (t, 2 H), pyrazolo|1,5-a|pyridin-2-yl)-amide 5-((5)- |1.92 - 2.09 (t, 1 H) , 1.57 - 1.74 (t, 7-ethyl-6-methyl-5,6,7,8-1 H), 1.30 (5.6 H), 1.10 (a, C H) .

Ma o) X 1 H), 8.42 (5, 1 H), 8.30 (a, 9-91 Hu,

TY r o 1 H), 8.16 (a, 9U-3.8 Hz, 1 H), 7.44 (a,

M M 0 U-2.0 Hz, 1 N), 7.13 (ai, 9U-8.8, 2.3 136-0 Khm Hz, 1 N), 6.74 (4, 923.5 Hz, 1 Sh), 6,681. 7772

M o nn (5, 1 H), 5.51 (5, 2 H), 2.84 (I, U-5.4

Hz, 2 N), 2.71 (Her, 95.7 Hz, 2 N), 2.41

B-tert-butylisoxazol-3-yl)-amide 5-(7-(5, C H), 1.34 (5, 9 H)

methyl-5,6,7,6-tetrahydro-pyridoyl3,4-α|pyrimidin-4-yloxy)-indole-1-carboxylic acid (DMSO-db) 5 ppm 11.21 (5.1 mM. ,o H), 8.42 (5, 1 H), 8.28 (a, 4-9.09 Hz, also If; i 1 H), 8.15 (4, U-3.79 Hz, 1 H), 7.44

M. M also, (9, 9-2.53 HZ, 1 H)U, 7.12 (49, U-8.97, uche 2.40 HZ, 1 H), 6.74 (y, U- 3.54 Hz, 1 that H), 6.65 (5, 1 H), 3.66 (4, 9-5.05 Gu, 136-H FI on 2 H), 3.06 - 3.17 ( t, 1 H), 2.92 (da, |. 779 9u-17.05, 4.67 Hz, 1 H), 2.53-2.62 (5-cyclopropylisoxazol-3-yl)-amide 5- (t, 2 H), 211-223 (t, 1 H), 1,43- ((5)-6-methyl-7-propyl-5,6,7,8- 1,61 (t, 2 H ), 1.01 -1.13 (t, 5 H), tetrahydropyrido|3,4-4|pyrimidine-4- 0.82 -0.98 (t, 6 H), (a, U-6.06 Hz, C yloxy)-indole-1-carboxylic acid H), 0.90 -0.97 (t, 2 H) (DMSO-db) 5 ppm 10.62 (5, 1

М. H), 7.42 (4,

M. M M uCh-2.3 Hz, 1 N), 7.10 (yes, 9-9.0, 2.4 uche Hz, 1 N), 6.70 (a, 9-3.5 Hz, 1 H), 6.27 me o y (5, 1 H), 4.09 (i, U-6.9 Hz, 1 H), 3.66 136-1 (b. 5., 2 H), 3.06 - 3.17 (t, 1 MN), 486.1

C 2.92 (ad, 9-17.2, 4.6 Hz, 1 H), 2.65 - (44-dimethyl-5,6-dihydro-4H-pyrrolo|1,2- 2.17 (t, 1 H), 2.52 - 2.64 (t, 2 H), ripyrazol-2-yl)-amide 5-((5)-7-ethyl-b- 00229 72.98 (t, C H), 1 ,92 (5, 6 M), methyl-5,6,7,8-tetrahydropyridoi|3,4- 1,09 (overlapping ad, -6,8 aIpyrimidin-4-yloxy)-indole-1-carbon / U; Z Well, 1.06 (, that

ACID overlaps, .)-6.8 Hz, Z H). (DMSO-db6) 5 ppm 11.24 (5.1 mo H), 8.42 (5.1 H), 8.27 (a, 9-9.0 HZ, 1 "e UA H ), 8.15 (a, 9-3.7 Hz, 1 N), 7.45 (4,

M. i m (ie, Ch-2.3 HC, 1 H), 7.13 (aa, 94-90, 2.4

Hm z-d Hz, 1 H), 6.75 (a, U-3.8 Hz, 1 H), 6.66 as (5, 1 H), 3.75 (9, 4-17.6 Hz , 1 N), 1365 LI o n 3.48 (а,9-17.6 Hz, 1 N), 29144, | 9 -16.9, 4.0 Hz, 1 H), 2.72 (49, (5-cyclopropylisoxazol-3-yl)-amide 5-y-12.5, 6.4 Hz, 1 H), 2 ... tetrahydropyrido|3,4-4|pyrimidine-4- (t, 1 H), 1,16 (a, U-6,3 Hz, C H), 1,03 yloxy)-indole-1-carboxylic acid -1112 (t.2N), 0.91-0.99 (t.2N

Mao SE (DMSO-db) 5 ppm 11.43 (5.1

That's If; DA H), 8.42 (5, 1 H), 8.28 (a, 4-9.09 HZ,

M. M still, 1 H), 8.15 (d, 9-3.79 HZ, 1 H), 7.45 uche (9, 9-2.53 HZ, 1 H), 7.14 (49, U-8.84, m» o v 2.27 HZ, 1 N), 7.04 (5, 1 N), 6.77 (a, 93.54 Gu, 1 N), 3.73 - 3, 84 (t, 2 N), 136-K - 3.17 - 3.93 (t, 1 N), 2.94 (99, 553.2 u-17.43, 5.31 Hz, 1 N), 2.54 - 2.63 (5-(1-trifluoromethyl-cyclopropyl)-(t, 1 H), 2.458 - 2.47 (t, 2 H), 1.54 - isoxazol-3-ylI-amide 5- ((5)-7- 1.59 (t, 4 H), 1.07 (0, 956.57 Hu, C cyclopropylmethyl-b6-methyl-5,6,7,8- H), 0.86 - 0.93 (t, 1 H), 0.51 (a, tetrahydro-pyrido|3,4-a|pyrimidine-4- -8.34 Hz, 28), 013-017 (t, 2 H) yloxy) -indole-1-carboxylic acid compound X (DMSO-sv) b parts/million 11.21 (5.1

S M iso H), 8.42 (5, 1 H), 8.27 (a, U-8.8 Hz, 1

IR H), 8.15 (a, 9U-3.8 Hz, 1 H), 7.44 (y,

Hm 92.3 Hu, 1 H), 7.13 (da, 9U-9.0, 2.4 136-I. M o nn Hu, 1 H), 6.75 (a, 9U-3.8 Hz , 1 H), 6.65 4452

C (5.1 N), 3.57 (5.2 N), 2.71 - 2.90 (t, 4 N), 2.59 (4, 95-71 Hz, 2 N), 2.10 - (5-cyclopropylisoxazol-3-yl)-amide 5-(7- | 2.22 (t, 1 H), 1.02 -1.19 (t, 5 H), ethyl-5,6,7, 8-tetrahydropyrido3,4- 0.86 - 0.98 (t, 2 H). α|pyrimidin-4-yloxy)-indole-1-carboxylic acid

Example 137 137-А. 1-15-(6-Hydroxymethylpyrimidin-4-yloxy)-indol-1-yl|-ethanone.

Gee)

Su

Mo u. but about

Man (1.74 g, 43.5 mmol) and acetic anhydride ( 5.13 ml, 54.3 mmol). After 1 hour the reaction is stopped with an aqueous solution of ammonium chloride and extracted with EAs. Most of the impurities are removed by passing through a column with silica gel eluting with a 50:50 mixture of heptane(OAc) and crude 1-(5-(b-benzyloxymethylpyrimidin-4-yloxy)-indol-1-yl|-ethanone is obtained. Then its dissolved in TFC (300 ml) and heated at 100 "C for 2 h. Then the solvent was removed and 1-(5-(6-hydroxymethylpyrimidin-4-yloxy)-indol-1-yl| ethanone was purified by means of KFC, eluting with by means of E(Ac. MS (ER) t/2 284.0 (M-n1). 137-8B. Tert-butyl ether of 16-(1H-indol-5-yloxy)-pyrimidin-4-ylmethyl|-methylcarbamic acid (c) shk;

Mu M re o

M m

M5CIII (3.27 ml, 41.9 mmol) and triethylamine (7.79 mL, 55.9 mmol), then DMAP (0.342 g, 2.80 mmol). The reaction mixture is then stirred for 1 h at 0 "C. Then water and the reaction mixture are added extracted with EOAc To a solution of the concentrated product (11.2 g, 31.0 mmol) in THF (1000 mL) was added methylamine (2 M in THF) (465 mL, 930 mmol) and the reaction mixture was stirred for 24 h. the solvent is removed and then the residue is redissolved in

DCM (300 mL) and added BOC anhydride (8.64 mL, 37.2 mmol). After 10 hours the solvent is evaporated and the residue is purified by means of KFC eluting with a mixture of heptane:eETOAc from 100:0 to 50:50 and the desired compound is obtained. MS (ER) t/2 355.1 (M.n-1). 137-6. (5-Isopropyl-1H-pyrazol-3-yl)-amide 5-(6-methylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid. s o x X ! (TC » Yen

M. 2 M and

M

16-(1H-indol-5-yloxy)-pyrimidin-4-ylmethyl|-methylcarbamic acid tert-butyl ether (300 mg, 0.846 mmol) was dissolved in DMF (8.46 mL), cooled to 0 °C and purged with nitrogen Add

Mann (102 mg, 2.54 mmol). The reaction mixture was stirred in an ice bath for 30 min., then the compound of Example 5-E (439 mg, 1.270 mmol) in b ml of DMF was added. After 2 hours the reaction mixture is cooled in an ice bath and diluted with 15 ml of ethyl acetate and the reaction is stopped with 2 ml of saturated ammonium chloride solution. The mixture is diluted with ethyl acetate and placed in a separatory funnel. The organic layer is separated and the aqueous layer is extracted with another ml of ethyl acetate. The combined organic substances are dried and concentrated. The solid substance is dissolved in 10 ml of DCM, cooled to 0 "C and treated with 2 ml of TFC. The ice bath is removed after 30 min. and after another 1 h. the reaction mixture is concentrated and then diluted with 10 ml of ethyl acetate. The solution is treated as with 3 mL of ammonium hydroxide. The solution was re-concentrated to give a white solid. The solid was absorbed on silica and separated by flash chromatography (0-10 95

MHz/Meon:DxHM) and get the desired compound. MS (IER) t/2 406.0 (M--1). "NNMME. (400 MHz, DMSO-dv) b frequency/million 12.22 (Bg. 5., 1 H), 10.59 (Bg. 5., 1 H), 8.65 (y, 9- 1.01 Hz, 1 H), 8.32 (y, 9-9.09 Hz, 1 H), 8.18 (y, 9U-3.79 Hz, 1 H), 7.45 (y, 9 -2.53 Hz, 1 N), 7.11 (yes, 9-8.84, 2.53 Hz, 1 N), 7.03 (a, 9-1.01 Hz, 1 N), 6, 72 (y, uU-3.28 Hz, 1 N), 6.34 (5, 1 N), 3.71 (5.2 N), 2.96 (Y, 9U-7.07 Hz, 1 N ), 2.29 (5, Z H), 1.25 (y, U-6.82 Hz, 6 H).

The following compounds are obtained by a similar method or by a method similar to that described in Example 19, Example 112-O and/or Example 76-0. gai o x (DMSO-4v) b freq./million 10.64 (bBg. 5.,

SM 1 N), 8.65 (5, 1 N), 8.30 (a, U-8.8 Hz,

M U. ground 1 N), 8.16 (a, 9U-3.5 Hz, 1 N), 7.45 (a,

M 9-2.3 Hz, 1 N), 7.12 (yes, 9-8.8, 2.5 137-0 M o n Hz, 1 N), 7.03 (5, 1 N), 6 .72 (4, 923.5. 732

H Hz, 1 H), 6.27 (5.1 H), 4.04- 4.14 (4,4-dimethyl-5,6-dihydro-4H-pyrrolo|1,2- (t, 2 H ), 3.70 (5.2 N), 2.31 - 2.38

B|pyrazol-2-yl)-amide 5-(6-(t, 2 H), 2.29 (5, C H), 1.32 (5.6 H) methylaminomethylpyrimidin-4-yloxy)-indol- 1-carboxylic acid "more; (DMSO-dv) 6 ppm 8.66 (y, "Me If; and 9-1.01 Hz, 1 H), 8.32 (4, 929.09 Hz,

M. and M Io; 1), 8.17 (a, 9-3.79 Hz, 1 N), 7.47

M. M (a, 9U-2.53 Hz, 1 H), 7.14 (da, 137-E in! M 3-8.84, 2.27 Hz, 1 H), 7.04 (a, 419.0

Nm H U-1.01 Hz, 1 N), 6.76 (a, 9-3.79 Hz,

And 1 H), 6.67 (5, 1 H), 3.73 (5,2 H), (5-(1-methylcyclopropyl)-isoxazol-3-yl|-. | 2.29 (5, C H) . )-indole-1-carboxylic acid (DMSO-dv) 6 parts per million 12.24 (bg.

M. and; 5.,1 H), 10.56 (Bu. 5., 1 H), 8.65 (a,

Ty du U-1.01 Hz, 1 N), 8.31 (a, 9U-9.09 Hz, which is 1 n), 8.17 (a, 4-3.79 Hz, 1 N), 7.44 (a, 9U-2.02 Hz, 1 N), 7.11 (a, 9-9.09 equal to and Hz, 1 N), 7.034, Hz.) ССО 6.71 (a, 9-3.54 Hz, 1 N), 6.22 (5.1

I I I I H), 3.71 (5, 2 H), 2.29 (5, C H), 1.88 (5-cyclopropyl-1 H-pyrazol-3-yl)-amide 5- |. 4 95 (t, 1 H), 0.84 - 0.99 (t, 2 (b-methylaminomethyl-pyrimidin-4-yloxy)- H), 0.72 (aa, 94.80, 2.02 Gu, 2 n indole-1-carboxylic acid o (DMSO-dv) 6 ppm 12.22 (bBg. gad x 5., 1 N), 10.59 (5, 1 N), 8.67 (a,

MH U-1.01 Hz, 1 N), 8.32 (a, 9U-9.09 Hz,

M M M 1 H), 8.19 (a, 9U-3.54 Hz, 1 H), 7.46 137-0 rya (a, 9U-2.53 Hz, 1 H), 7.11 - 7 ... 34 (5.1 H), (B-isopropyl-1H-pyrazol-3-yl)-amide 5-(6-a gz How are they and CI in dimethylaminomethyl-pyrimidin-4-yloxy)-vn) indol-1- carboxylic acid

Mi o X (DMSO-4v) 6 parts/million 10.73 (bBg. her 7 -K 5., 1 H), 8.65 (a, 9-1.01 Hz, 1 H),

M M zd 8.32 (y, 9U-8.84 Hz, 1 H), 8.22 (y, rya 9EZ,54 Hz, 1 H), 7.78 (y, 9-2.53 Hz, 137 -N. | NM o nn 1 H), 7.44 (a, 20-2.53 Hz, 1 H), 7.10 | 4201 -7.12 (t, 1 H), 7.03 (y, 951.01 Hz, . . . 1 H), 6.71 (a, 9-3.03 Hz, 1 H), 6.52 uethylamomethyl pyrimidine ooo o ayay t yu ZTo(t NI, . . 2.28 (in, C H), 1.54 (5.9 H) of indole-1-carboxylic acid more) (DMSO-yv) 6 part./ million 12.22 (bBg. g IF; and 8.1 N), 10.59 (bg. 8., 1 N), 8.65 (4,

M. z M MN 9-1.0 Hz, 1 N), 8.26 - 8.41 (t, 1 N), r M 8.17 (r. 5., 1 N), 7.42 (horn 5., 1 N), 7.06 - 7.13 (t, 1 N), 7.04 (5.1 N), 1377 nm OH 670 (bg. 8.1), 626 - in (t,1 | 2

AK H), 3.79 (5, 2 H), 2.86 - 3.04 (t, 1

H), 2.04 -2.16 (t, 1 H), 1.24 (y, (5-isopropyl-1H-pyrazol-3-yl)-amide 5-(6-|9-6.6 Hz , 6 H), 0.30 - 0.40 (t, 2 H), cyclopropylamino-methylpyrimidine-4- 0.21-0.27 (t, 2 H) yloxy)-indole-1-carboxylic acid (DMSO- yv) 6 parts/million 12.22 (bBg.

Mo zh 5., 1 H), 10.58 (5, 1 H), 8.66 (a, (y MH 91.01 Hz, 1 H), 8.32 (y, 9-9.09 Gu,

Mo M -k 1 H), 8.18 (a, 9-3.79 Hz, 1 H), 7.45 re M (d, 9-2.53 Hz, 1 H), 7.07 (a, 951.01 137th NM o nn Hz, 1 H), 7.11 (aa, d-8.84,2.53 Hz, | 4201 1 H), 6.72 (y, 9-3.54 Hz , 1 H), 6.34 p, (5, 1 H), 3.79 (5, 2 H), 2.97 (y, (5-isopropyl-1H-pyrazol-3-yl)-amide 5- (6- 176.57 Hz, 1 H), 2.57 - 2.59 (t, ethylaminomethyl-pyrimidin-4-yloxy)- 28), 1 25 (y, U-7.07 Hz, 6 H), 1.03 indole-1-carboxylic acid (6 5-7.07 Hz, Z H)

M. 0 (DMSO-yv) 6 ppm 12.22 (bBg. g IF; A 8., 1 H), 10.58 (c, 1 H), 8.64 (a,

M. M MN U-1.01 Hu, 1 H), 8.32 (4, U-8.84 Hu, p M 1 H), 8.18 (a, 9-3.79 Hz, 1 H) , 7.44 o! y (y, 9-2.53 Hz, 1 N), 7.11 - 7.12 (t, 137-K NM 1nH) 7.06 (a, 9U-1.01 Hz, 1 N), 6, 71 4342 (y, 9-3.28 Hz, 1 N), 6.34 (а, 9-1.26

Hz, 1 H), 3.74 (5.2 H), 2.95 (y, 9U-7.07 Hz, 1 H), 1.40-1.43 (t, 2H), (5-isopropyl -1H-pyrazol-3-yl)-amide 5-(6- 11.25 (a, 9-7.07 Hz, 6 H), 1.22 (Bg. 5., propylaminomethyl-pyrimidin-4-yloxy) - 1 N), 0.81 -0.88 (t, 4 N) of indole-1-carboxylic acid m. 0 (DMSO-yv) 6 parts/million 12.21 (bBg.

There is If; A 8.1 N), 10.58 (5.1 N), 8.65 (8.1 MN),

M. Ж M МН 8.32 (y, 9U-8.84 Hz, 1 H), 8.18 (a, according to M tn tod- tt ya, "7.04-7, t, 7, ; 137 | nm on 9-8.84 Hz, 1 H), 6.72 (a, 923.54 Hz, | 7372

A 1 H), 6.34 (5, 1 H), 3.79 (5.2 H), 2.94 - 2.99 (t, 1 H), 2.73 - 2.76 (t, ( 5-isopropyl-1H-pyrazol-3-yl)-amide 5-I6-|H), 1.25 (4, 2-6.82 Hz, 6 H), 1.00 (isopropylaminomethyl)-pyrimidine-4 - (ad, 9-6.32 Hz, 6 H) yloxy|-indole-1-carboxylic acid

M. 0 (DMSO-yv) 6 parts/million 12.21 (bBg. g If; I 8., 1 H), 10.58 (5, 1 H), 8.64. (and,

M. Ж M ш МН 91.01 Hz, 1 H), 8.32 (y, 9-8.84 Hz, r M 1 H), 8.18 (y, 9-3.54 Hz, 1 H) . 1 H), 6.72 446.2 (a, 9-3.54 Hz, 1 H), 6.34 (5.1 H), 3.68 (5, 2 H), 3.17 (y, 95.31 Hz, 1

NU, 2.95 (y, 9-6.57 Hz, 1 H), 2.02 - (5-isopropyl-1H-pyrazol-3-yl)-amide 5-(6- /|2.09 (t , 2 H), 1.51-1.72 (t, AN), cyclobutylamino-methylpyrimidine-4- 1.25 (a, 9-7.07 Hz, 6 H) yloxy)-indole-1-carboxylic acid ( DMSO-dv) 6 ppm 8.65 (i,

M y; 9-1.01 Hz, 1 N), 8.30 (y, 9-9.09 Hz,

Ty Do. 1 H), 8.16 (a, 9-3.79 Hz, 1 H), 7.44 that U - (a, 9-2.02 Hz, 1 H), 7.11 (aa, 3-8 .84, 2.27 Hz, 1 N), 7.02 (y, morinie o i Che1.01 Hz, 1 N), 6.71 (a, 923.03 Hz, |. 718 1N), 6.16 (5, 1 H), 3.79 (in, C H),

I I 13.70 (in, 2 H), 2.28 (5, C H), 1.81 - (5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)- 1.99 (t , 1 H), 0.96 - 0.99 (t, 2 H), 5-(b-methylaminomethylpyrimidine-4- 0.59 - 0.73 (t, 2 H) yloxy)-indole-1-carboxylic acid acid

R SHE

Ma U with E (DMSO-ov) b frequency/million 8.66 (a, (y s - 91.01 Hz, 1 H), 8.32 (y, 9-9.09 Gu,

MM urine 1 H), 8.18 (a, 9-3.79 Hz, 1 H), 7.47 137-O re (a, 9-2.53 Hz, 1 H), 7.13 (y , y-2.53 4461

NM o nn Hz, 1 H), 7.04 (a, 9-1.01 Hz, 1 H), " 7.07 (5, 1 H), 6.76 (j, 9-3.79 Hz, 1 (1-methyl-5-trifluoromethyl-1H-pyrazol-3-zn, (5, C H), 3.72 (8, 2 H), 2.29 yl)-amide 5-(b-methyl-aminomethylpyrimidine -| "" 4-yloxy)-indole-1-carboxylic acid

There is phi;

I sx E (DMSO-4b) b freq./million 8.65 (a,

M M -k U 91.01 Hz, 1 H), 8.31 (y, U-8.84 Gu, rya ME 1 H), 8.20 (a, 2-3.79 Hz, 1 H) . ), 6.72. |. b a, 94.29 Hz, 1 H), 6.51 (5.1 H (p-methyl-1-(2,2,2-trifluoroethyl)-TH- t97 c BoB(t,2 Nu, zy ( c, 2 p, pyrazol-3-yl|-amide 5-(6- | | 2.26 - 2.35 (t, 6 H) methylaminomethylpyrimidin-4-yloxy)-indole-1-carboxylic acid

M.,O (DMSO-dv) 6 parts/million 8.66 (y, "Me IF; A 921.01 Hz, 1 H), 8.32 (a, 2-9.09 Gu,

M. and M Sh o 1 H), 8.17 (ai, 9-3.79 Hz, 1 H), 7.47 r M (а, 9-2.53 Hz, 1 H), 7.14 ( aa, 137-0 o y 98.97, 2.40 Hz, 1 N), 7.04 (5.1 N), | 407.1 tu 6.76 (a, 9-3.79 Hz, 1 H), 6.69 (5, 1

H), 3.73 (5.2 H), 3.07 - 3.14 (t, 1 (5-isopropylisoxazol-3-yl)-amide 5-(6- H), 2.30 (5, C H), 1.28 -1.31 (t, 6 methylaminomethylpyrimidin-4-yloxy)-H indole-1-carboxylic acid m. o (DMSO-dv) 6 parts/million 8.66 (5, 1

E U A H), 8.32 (a, 4-9.09 Hz, 1 H), 8.16 (4,

M» M (in; 23.79 Hz, 1 H), 7.46 (a, 922.53 Hz, in 1 H), 7.13 (a9, 9-8.97, 2.40 Hz, 1 137 -8 M H), 7.04 (in, 1 H), 6.74 (9, 9-3.79 Hz, |. 405.1

Nm o n 1 N), 6.65 (in, 1 N), 3.71 (5.2 N),

I 2.29 (b, C H), 2.13 - 2.20 (t, 1 H), (B-cyclopropylisoxazol-3-yl)-amide 5-(6-|1.08 (ai, U- 8.46, 2.65 Hz, 2 H), 0.94 methylaminomethyl-pyrimidin-4-yloxy)- | (yes, 954.80, 2.53 Hz, 2 N). indole-1-carboxylic acid

Mao SE and M r Z (DMSO-4v) b frequent./million 12.79 (Bg.

M» M МН 8.,1 H), 8.66 (5, 1 H), 8.32 (4, at 428.84 Hz, 1 H), 8.18 (bg. 5., 1 H), 7 AB (9, 922.27 Hz, 1 N), 7.12 (yes, 137-5 | NM o nn h-8.97,2.40 Hz, 1 N), 7.04(5.1 8 ), |: 6.73 (4.9-3.28 Hz, 1 H), 6.67 (bg. 5., (B-(1-trifluoromethyl-cyclopropyl)-1H- | 1 H), 3, 72 (5, 2 H), 2.30 (5, C H), pyrazol-3-ylI-amide 5-(b-methylaminomethyl- | 1.40 (bg. 5., 2 H), 1.29 ( g. 5.2 N) pyrimidine-4-yloxy)-indole-1-carboxylic acid "more (DMSO-dv) 6 ppm 8.65 (y, with X 921.01 Hz, 1 N), 8.30 (a, 49.09 Hz, which is Fa; y |tnuvit a, on3.5a Gu, 1 H), 747 y (a, U-2.27 Hz, 1 H), 7.14 (99,

M 4-8.97, 2.40 Hz, 1 H), 7.07 (5, 1 H), 137t NM o nH 6.76 (a, 9-3.79 Hz, 1 H), 6.655,1.1 .7790 and N), 3.78 (5, 2 N), 3.38 (and, 925.56 Hz,

MeO 2 H), 3.22 (5, C H), 2.68 (i, 95-5.68 (B-cyclopropylisoxazol-3-yl)-amide 5-(6- | Hz, 2 H), 2 .14 -2.21 (t, 1 H), 1.06 ((2-methoxyethylamino)-methyl|-pyrimidine- | - 1.11 (t, 2 H), 0.92 -0.97 (t, 2 H) 4-yloxy)-indole-1-carboxylic acid

M., 0

There is If; A (DMSO-ov) b frequency/million 8.65 (4,

M» M M- 921.01 Hz, 1 H), 8.31 (a, 4-9.09 Hz,

In 1 n), 8.17 (a, 94-3.79 Hz, 1 H), 7.44 (a, 9-2.02 Hz, 1 H), 7.11 (99, 137-0. | Nm o n 928.97, 2.0 Hz, 1 N), 702 (4, 3922

Ch-1.01 Hz, 1 H), 8.72 (a, 923.03 Hz, (1,5-dimethyl-1H-pyrazol-3-yl)-amide 5-(6- | 1 H), 6 ,34 (5, 1 H), 3,67 - 3,71 (t, 5 methylaminomethyl-pyrimidin-4-yloxy)- | H), 227 - 2,30 (t, 6 H) of indole-1-carboxylic acid (c) (DMSO-dv) 6 ppm 8.66 (y, mo 921.01 Hz, 1 H), 8.33 (a, 4-9.09 Hz, is X 1 H), 8, 18 (a, 923.79 Hz, 1 H), 7.47 that I; o (a, 9-2.53 Hz, 1 H), 7.14 (yes, gray 48.97, 2.40 Hz, 1 H), 7.05 (5, 1 H), 137-U Khm 6 .75-6.78 (t, 2 H), 6.30-6.31 (t, 463.2

NM o nn 1 H), 3.71 - 3.77 (t, 4 H), 3.46 (ada, 9-11.75, 8.59, 2.91 HC, 2 H),

I5-(4-methyltetrahydropyran-4-yl)- 2.30 (5, C H), 2.05 (y, Y-9.85 Hz, 2 isoxazol-3-ylI-amide 5-(6- H) , 164 -1.71 (t, 2 H), 1.34 (5, C methylaminomethylpyrimidin-4-yloxy)-H) indole-1-carboxylic acid

(DMSO-dv) 6 ppm 12.13 (5, 1 "still; H), 10.57 (rg. in5., 1 H), 8.65 (a,

Ty - M U-1.01 Hz, 1 N), 8.32 (a, 9U-9.09 Hz,

M. Ж M and МН 1 H), 8.18 (a, 9-3.54 Hz, 1 H), 7.44

M M (a, 9U-2.53 Hz, 1 H), 7.11 (da, 137-M M y-8.97, 2.40 Hz, 1 H), 7.03 (a, 418.2

NM o n U-1.01 Hz, 1 N), 6.71 (a, 9-3.79 Hz, 1 N), 6.30 (a, U-2.02 Hz, 1 N), 3, 71 (5-(1-methylcyclopropyl)-1 H-pyrazole-3-yl- (5, 2 H), 2.29 (5, C H), 1.41 (5, C H), amide 5-( b-methylaminomethylpyrimidine-4- | 0.91 - 0.95 (t, 2 H), 0.76 - 0.80 (t, yloxy)-indole-1-carboxylic acid 2 H).

Mao x (DMSO-dv8) b parts/million 10.64 (5, 1 (y a - H), 8.65 (a, 9U-1.01 Hz, 1 H), 8.31 (a,

Mo M -k 3-8.84 Hz, 1 H), 8.20 (a, 9-3.79 Hz, re M 1 H), 7.44 (a, 9-2.53 Hz, 1 H) , 7.11 137-X NM o NN (ad, 9U-8.97, 2.40 Hz, 1 H), 7.02 (5.1 | 4202

H), 6.70 (a, 9U-3.79 Hz, 1 H), 6.33 (5,

I , , , 1 H), 4.37 - 4.58 (t, 1 H), 3.70 (5.2 (1-isopropyl-o-methyl-1 H-pyrazol-3-yl)- H) . -1-carboxylic acid he pf; SEZ du (DMSO-du) b frequent./million 8.67 (5, 1

M. 22 M y o H), 8.35 (y, 9U-9.09 Hz, 1 H), 8.16 (a, rya M y3-3.54 Hz, 1 H), 7.46 (a , 9-2.27 Hz, 137-U NM o nn 1 NN), 7.13 (yes, 9U-8.97, 2.40 Gu, 1 473.2

H), 7.04 (a, 9-5.31 Hz, 2 H), 6.74 (a,

And 3-3.79 Hz, 1 H), 3.77 (5.2 H), 2.30 - (5-(1-trifluoromethyl-cyclopropyl)- 2.34 (t, C H), 1.50 - 1.59 (t, 4 n isoxazol-3-yl|-amide 5-(6-methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid water exactly (DMSO-dv) 6 parts/million 8 .67 (5, 1

М. y, 9-2.53 Hz, 4591 nm o nn 1 H), 7.07 - 7.13 (t, 2 H), 7.03 (5, 1 2 NU, 6.71 (a, 9U-3 .79 Hz, 1 N), 3.85 (5,

I5-(1-trifluoromethyl-cyclopropyl)-2 H), 1.49-1.57 (t, 4 H) isoxazol-3-yl|-amide 5-(6-aminomethylpyrimidin-4-yloxy)-indol-1 - carboxylic acid (DMSO-dv) 6 ppm 10.64 (bg. 5., 1 N), 8.65 (5.1 N), 8.30 (a,

That is: x and 3-9.09 Hz, 1 H), 8.17 (a, 9-3.79 Hz,

M. z M MU 1 H), 7.44 (a, 9-2.53 Hz, 1 H), 7.11 r M (ai, 9U-8.97, 2.40 Hz, 1 H), 7 .03 (a, 137-AA M U-1.01 Hz, 1 H), 6.71 (a, 9-4.29 Hz, | 4322

NM o n 1 NN), 6.16 (c, 1 H), 4.15 (a, 9-7.24

Hz, 2 H), 3.72 (5.2 H), 2.30 (5.3 H), (5-cyclopropyl-1-ethyl-1H-pyrazol-3-yl)- | 1.93-1.98 (t, 1 H), 1.32-1.43 (t, C amide 5-(b-methylaminomethylpyrimidine-4- | H), 0.93-1.04 (t, 2 H), 0.60-0.73 (t, yloxy)-indole-1-carboxylic acid 2 H)

(DMSO-av) b frequency/million 10.64 (bBg.

Ma o); x 5.1 N), 8.65 (y, 9U-1.01 Hz, 1 N),

Th - m-th 8.30 (a, 9U-8.84 Hz, 1 N), 8.16 (a,

M. M that 9-3.79 Hz, 1 N), 7.44 (a, 9-2.53 Hz, 137-AB rya M 1 nH), 7.10 (da, 9U-8.84, 2 ,53 Gu, 1 4442

NM o nn H), 7.02 (5.1 H), 6.70 (a, 9U-3.79 Hz, " 1H), 6.16 (5.1 H), 3.70 (5.2 N),

I I I .13.57-3.63 (t, 1 H), 2.28 (5.3 H), (1 u-dicyclopropyl-1 H-pyrazol-3-yl)-amide 2.03-2 .10 (t, 1 H), 0.99-1 2 (t, 6 5-(β-methylaminomethyl-pyrimidine-4-H), 0.69-0.74 (t, 2 H) yloxy)-indole -1-carboxylic acid (DMSO-α) b part./million 10.66 (bBg.

M o 5., 1 H), 8.66 (5, 1 H), 8.91 (a,

That is: x I 3-8.84 Hz, 1 H), 8.19 (a, 9U-3.54 Hz,

M. z M M 1 H), 7.44 (a, 9-2.27 Hz, 1 H), 7.10 137-AS M M (ad, U-8.97, 2.40 Hz, 1 H ), 7.03 (5.1

M H), 6.70 (a, 9U-3.03 Hz, 1 H), 6.17 (5.I 4462

NM on 1 H), 4.76 (quintet, U-6.57 Hz, 1 H), 3.73 (5, 2 H), 2.30 (5, C H), 1.86- (B- cyclopropyl-1-isopropyl-1H-pyrazole-3- | 2.00 (t, 1 H), 1.42 (y, U-6.57 Hz, 6 yl)-amide 5-(b-methylaminomethylpyrimidine- | H ) 0.91-1.04 (t, 2 H), 0.60-0.72 (t, 4-yloxy)-indole-1-carboxylic acid 2 H)

IS

Mao with E (DMSO-dv) 5 ppm 8.65 (4,

Ty dl i- 9-1.26 Hz, 1 N), 8.31 (a, 9U-8.84 Hz,

М. yes

NM o NN 98.97, 2.40 Hz, 1 N), 7.03 (a, 486.2

U-1.01 Hz, 1 H), 6.73 (a, 9-3.03 Hz, 1 H), 6.66 (5, 1 H), 3.83 (5, C H),

PP-methyl-5-(1-trifluoromethyl- | 3.70 (5, 2 H), 2.29 (5, C H), 1.49 - cyclopropyl)-1 H-pyrazol-3-yl|-amide 5-(6-1.52 (t, 2H), 1.30 - 1.34 (t, 2n) methylaminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid o (DMSO-а) b chat ./million 10.62 (bBg.

Ma X 5.1 H), 8.66 (y, 9U-1.01 Hz, 1 H), (y s - 8.32 (a, 9U-8.84 Hz, 1 H), 8.17 (and,

M M CHI y-3.54 Hz, 1 H), 7.45 (a, 9-2.02 Hz, 137-AE rya 1), 7.11 (da, Y-8.97, 2.40 Gu , 1 4202

NM o nn H), 7.03 (a, 9-1.01 Hz, 1 H), 6.72 (a, ' 9-3.03 Gu, 1 H), 6.36 (5, 1 H) . ; c, ) yloxy)-indole-1-carboxylic acid

Example 138 138-A. (4,4-Dimethyl-5,6b-dihydro-4H-pyrrolo|1,2-b|pyrazol-2-yl)-amide 5-(6-methanesulfonylmethylpyrimidin-4-yloxy)-indole-1-carboxylic acid. (c) with input

M. Fa y, y, zh ho o nn

It is obtained by a method similar to that described in example 86A. MS (ER) t/2 481.0 (M--1); IN NMR (400 MHz, DMSO-av) b frequency/million 10.65 (5, 1 N), 8.77 (5, 1 N), 8.31 (y, 9U-8.8 Hz, 1 N ), 8.16 (a, 9-3.5 Hz, 1

H), 7.49 (y, 9-23 Hz, 1 H), 7.19 (5, 1 H), 7.15 (ai, 9U-9.0, 2.4 Hz, 1 H), 6 .73 (a, 9U-3.8 Hz, 1 N), 6.28 (5.1 N),

4.69 (5, 2 H), 4.09 (I, 9U-6.9 Hz, 2 H), 3.11 (5, Z H), 2.29-2.38 (t, 2 H) , 1.32 (5.6 N).

The following compounds are obtained by a similar method. 138-858. (5,6-Dihydro-4H-pyrrolo|1,2-b|pyrazol-2-yl)y-amide 5-(b-methane-sulfonylmethylpyrimidin-4-yloxy)-indole-1-carboxylic acid. pf 7

Mo mo | l

M o Kh-m z«:) (c) N

MS (ER) t/2 453.0 (M'-1); IN NMR (400 MHz, DMSO-dv) b freq./million 10.62 (5, 1 N), 8.78 (a, 9-1.0 Gu, 1 N), 8.32 (a, 90- 91 Hu, 1 H), 8.17 (a, 9-3.8 Hu, 1 H), 7.48 (a, 9-2.5 Hz, 1 H), 7.18 (a, U-1 ,0 Hz, 1 H), 7.14 (ad, 9U-9.0, 2.4 Hz, 1 H), 6.73 (y, 9U-3.8 Gu, 1 H), 6.28 ( 5, 1 N), 4.69 (5.2 N), 4.04 (I, 90-71 Hz, 2 N), 3.11 (5, Z

H), 2.88 (, 9-7.2 Hz, 2 H).

Example 139 139-А. (5-Cyclopropylisoxazol-3-yl)-amide 5-(7-methanesulfonyl-5,b,7,8-tetrahydropyridoi|3,4-a|pyrimidin-4-yloxy)-indole-1-carboxylic acid. (in)

Rava; and

M. my oh for

M o nn otvto

It is obtained by a method similar to that described in example 35. MS (IER) t/2 4951 (Ma1); "H NMR (400 MHz, DMSO-av) 5 ppm 11.22 (5, 1 N), 8.50 (5, 1 N), 8.28 (a, 9-91 Hz, 1 N) , 8.16 (a, 9U-3.8 Hz, 1

NO, 7.47 (y, 9-23 Hz, 1 H), 7.15 (yes, U-8.8, 2.3 Hz, 1 H), 6.76 (y, 9U-3.8 Hz , 1 H), 6.65 (5, 1 H), 4.39 (5.2 H), 3.57 (I, 9U-5.68 Hz, 2 H), 3.06 (5, Z H ), 2.96 (I, 925.7 Hz, 2 H), 2.12-2.25 (t, 1 H), 1.04-1.13 (t, 2 H), 0.89-0 .99 (t, 2 H).

The following compounds are obtained by a similar method. 139-8. 5-(7-Methanesulfonyl-5,6,7,8-tetrahydropyridoyl3,4-a|pyrimidin-4-yloxy)-indole-1-carboxylic acid (5-tert-butylisoxazol-3-yl)-amide. (c) seam; and

M. 2 m 1 6 w"

Mon.-Tue

MS (ER) t/2 511.2 (M--1); "H NMR (400 MHz, DMSO-av) 6 ppm 11.27 (5.1 N), 8.51 (5.1 N), 8.29 (a, 9-9.0 Hz, 1 H), 8.17 (a, 9-3.7 Hz, 1 H), 7.47 (a, 9-2.4 Hu, 1 H), 7.16 (aa, 9U-9.0, 2 ,3 Hz, 1 N), 6.77 (y, 3U-3.7 Hz, 1 N), 6.68 (5, 1 N), 4.39 (5, 2 N), 3.57 (I , Y-5.9 Hz, 2 H), 3.06 (5, C H), 2.96 (i, 2 H), 1.34 (5, 9 H). 139-6. (5-Cyclopropylisoxazole -3-yl)-amide 5-((5)-7-methanesulfonyl-b-methyl-5,6,7,8-tetrahydropyridoyl3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid. (c) vaf; i

M. 2 mm 1 6 already M mon otvto

MS (IER) t/2 509.1 (M--1); "H NMR (400 MHz, DMSO-av) 6 ppm 11.22 (5, 1 N), 8.51 (5, 1 N), 8.28 (a, 9-91 Hu, 1 N) , 8.16 (y, 9-38 Hz, 1 H), 7.47 (a, 9-2.3 Hz, 1 H), 7.16 (aa, 9U-9.0, 2.4 Hz, 1 H), 6.76 (a,

93.68 Hz, 1 H), 6.65 (5, 1 H), 4.29-4.63 (t, Z H), 3.06 (5, 4 H), 2.80 (a, 9U -16.9 Hz, 1 H), 2.10-2.27 (t, 1 H), 1.23 (a, 9-6.8 Hz, C H), 1.03-1.14 (t , 2 N), 0.89-0.99 (t, 2 N). 139-0.. 15-(1-Trifluoromethylcyclopropyl)-isoxazol-3-yl|1-amide. 5-(b-methane-sulfonyl-b,7-dihydro-5H-pyrrolo|3,4-4|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid. (6)

SSO av me

M. 2 M here

M X-m x -0 (6) H -Z o

MS (ER) t/2 549.15 (M--1); "H NMR (400 MHz, DMSO-av) b frequency/million 11.45 (5.1 N), 8.67 (5.1 N), 8.31 (a, 9U-8.84 Hz, 1 H), 8.17 (a, 2-4.04 Hz, 1 H), 7.50 (j, 2-2.78 Hz, 1 H), 7.18 (da, 2-8.97, 2 ,40 Hz, 1 N), 7.04 (5, 1 N), 6.79 (a, U-4.04 Hz, 1 N), 4.71-4.77 (t, 4 N) 3, 10 (5, Z H), 1.54-1.60 (t, 4 H).

Example 140 140-А. (5-Cyclopropylisoxazol-3-yl)-amide 5-((5)-6-methyl-7-methyl-carbamoylmethyl-5,6,7,8-tetrahydropyridoyl3,4-4|pyrimidin-4-yloxy)-indole -1-carboxylic acid. set! 7

M. 2 m 1 6

M m" he lake

Academy of Sciences

It is obtained by a method similar to that described in example 41-C. MS (IER) t/2 502.1 (MaА1); "N

NMR (400 MHz, DMSO-dv) 6 ppm 11.22 (5, 1 N), 8.43 (5, 1 N), 8.28 (a, 9-8.84 Hz, 1 N) , 8.15 (a, 9-3.79

Hz, 1 H), 7.82 (a, 9U-4.55 Hz, 1 H), 7.44 (a, 9-2.27 Hz, 1 H), 7.12 (da, 9U-8, 84, 2.27 Hz, 1 N), 6.75 (y, 9-3.79

Hz, 1 N), 6.65 (5, 1 N), 3.74 (y, 9-4.55 Hz, 2 N), 3.08-3.22 (t, C H), 3.00 (aa, 9U-17.05, 4.67 Hz, 1 H), 2.59-2.66 (t, 4 H) 2.09-2.24 (t, 1 H), 1.03-1 .15 (t, 5 N) 0.89-1.00 (t, 2 N).

The following compounds are obtained by a similar method. 140-8. (5-(1-Methylcyclopropyl)-1H-pyrazol-3-yl|-amide 5-(5)-6-methyl-7-methylcarbamoylmethyl-5,6,7,8-tetrahydropyridoyi3,4-4|Ipyrimidine- 4-yloxy)-indole-1-carboxylic acid. that's it

M. M MN r m" on lake

AMN

MS (ER) t/2 501.3 (M--1); "H NMR (400 MHz, DMSO-av) b freq./million 12.13 (5.1 N), 10.56 (5.1 N), 8.43 (5.1 N), 8.30 ( y, 9-91 Hz, 1 H), 8.17 (a, 9-3.5 Hz, 1 H), 7.83 (9, 9-43 Hz, 1 H), 7.41 (a, 9 -2.5 Hz, 1 H), 7.08 (aa, 9-9.0, 2.4 Hz, 1 H), 6.71 (a, 9U-3.5 Hz, 1 H), 6, 29 (5, 1 N), 3.68 (5, 2 N), 3.19 (5, 2 N), 2.87 (yes, 915.8, 4.7 Hz, 4 N), 2.64 (a, 9-45 Hz, with H), 1.41 (5, with H), 0.89-0.96 (t, 2 H), 0.72-0.82 (t, 2 H).

Example 141

Ethylamide (5)-4-11-(5-cyclopropylisoxazol-3Z-ylcarbamoyl)-1H-indol-5-yloxy|-6-methyl-5,8-dihydro-bH-pyridoyl3,4-4|pyrimidin-7- carboxylic acid.

(c) wav; 4! and

M. mm 1 6 in all m" on on

It is obtained by a method similar to that described in example 36, using ethyl isocyanate.

MS (IER) t/2 502.1 (M--1); reversible isomers exist at 27 "C in DMSO-yv6, "H NMR (400 MHz, DMSO-dv) b parts/million 11.22 (5.1 N), 8.49 (5.1 N), 8, 28 (a, 9U-9.09 Hz, 1 H), 8.15 (a, 9U-3.79 Hz, 1 H), 7.46 (a, 9-2.27 Gu, 1 H), 7 .15 (yes, 9-8.97, 2.40 Hz, 1 H), 6.75 (a, 9U-3.28 Hz, 1 H), 6.69 (I, U-5.18 Hz, 1 H), 6.65 (5, 1

H), 4.68-4.85 (t, 2 H), 4.14 (a, 9-18.95 Hz, 1 H), 3.11 (daa, 9U-7.26, 5.12, 2.53 Hz, 2 N), 2.88-2.99 (t, 1 N), 2.712-2.82 (t, 1 N), 2.12-2.23 (t, 1 N), 1 .02-1.13 (t, 8 N), 0.89-0.99 (t, 2 N).

Example 142 142-А. Methyl ether of 1-hydroxymethylcyclopropanecarboxylic acid. / (in) (6)

He

A solution of cyclopropane-1,1-dicarboxylic acid methyl ether (9 g, 62.4 mmol) in THF (180 mL) was cooled to 0 °C and triethylamine (9.7 mL, 69.6 mmol) and 3-methylbutyryl chloride ( 9.1 mL, 9.6 mmol) and the reaction mixture was stirred for 1 h. In a separate flask, sodium borohydride (7.1 g, 188 mmol) was dissolved in THF (100 mL)/H2O (25 mL) and cooled to 0 " WITH. The mixed anhydride is filtered through a funnel with a porous glass filter to remove salts obtained during the previous reaction, and added to a flask containing sodium borohydride, and the reaction mixture is stirred for 1 h. at 0 "C. 1 N HCl is added, and the product is extracted with EtOAc and then with a mixture of CClZnHrH2O. Then it is purified with the help of KFC, eluting with a mixture of heptane/Euds (from 100:0 to 20:80) and 1-hydroxymethylcyclopropanecarbonate methyl ether is obtained acid. "H NMR (400 MHz, DMSO-α) 6 ppm 4.61 (i, 9-5.81

Hz, 1 N), 3.59 (5, C H), 3.55 (y, 9U-6.06 Hz, 2 H), 1.01 (а, 2-3.03 Hz, 2 H), 1.01 (a, U-10.36 Hz, 1 N), 0.87 (a, 9-3.03 Gu, 1 N), 0.85-0.88 (t, 1 N). 142-8. 3-(1-Hydroxymethylcyclopropyl)-3-oxopropionitrile.

Me ar

He

To a solution of lithium diisopropylamide (115 mmol) in THF (300 ml), at -78 "С, a solution of methyl ether of 1-hydroxymethylcyclopropanecarboxylic acid (5 g, 28.4 mmol) in CH2ZSM (5.91 ml, 115 mmol) is added. Reaction the mixture is allowed to warm to RT. The reaction is then quenched with 1 N HCl (200 mL) and extracted with EAs (200 mL x 3 ). The mixture is then dried and evaporated to give 3-(1-hydroxymethylcyclopropyl)-3-oxopropionitrile. "H NMR (400 MHz, DMSO-4v) b frequency/million 4.26 (5.2 N), 4.03 (5.1 N), 3.58 (bg. 5.2 N) 1.15- 1.16 (t, 2 N), 0.92-0.95 (t, 2 N). 142-606. (1-(3-Aminoisoxazol-5-yl)-cyclopropyl|-methanol.

M

NOM

It is obtained by a method similar to that described above in example 7-A. MS (IER) t/2 155.2 (M.-1). 142-O0. Phenyl ether of 35-P1-(tert-butyldimethylsilanyloxymethyl)-cyclopropyl|-isoxazol-3-yl)-carbamic acid.

Yaya and

X and o 1 9

M

S, N

Imidazole (2.385 g, 35.0 mmol) and tert-butylchlorodimethylsilane (4.22 g, 28.0 mmol).

After 1 hour the reaction ends. After washing organic substances with 1 n. The NOSI organic substances are concentrated and then dissolved in THF (200 ml) at 0 "C and pyridine (3.62 ml, 44.7 mmol) and phenyl chloroformate (5.63 ml, 44.7 mmol) are added. After 1 h, the reaction is complete and the reaction is quenched with water. Next, the organics are extracted with EAs, dried and evaporated. The desired compound is then purified by HPLC, eluting with a mixture of heptane:EOAc from 100:0 to 90:10. MS (IR) t/2 389.0 (M-n1). 142-E. I5-(1-Hydroxymethylcyclopropyl)-isoxazol-3-yl)|-amide 5-(6,7-dihydro-5H-pyrroloi3,4-

Phipyrimidin-4-yloxy)-indole-1-carboxylic acid. oh he was; co

M Hmm

N o nn

To a solution of tert-butyl-4-(1H-indol-5-yloxy)-5H-pyrrolo|3,4-9|pyrimidine-6(7H)-carboxylate (2 g, 5.68 mmol) in DMF (50 ml ) at 0 "С add Mann (0.681 g, 17.0 mmol) and 55-(1-(tert-butyldimethyl-silanyloxymethyl)-cyclopropyl|-isoxazol-3-yl-carbamic acid phenyl ether (3.09 g, 7 .95 mmol). After 1 h, the reaction ends. After stopping the reaction with water, the organic substances are extracted with EtOAc and the fractions are combined, dried and evaporated. The crude product is dissolved in THF (10 ml) at 0 "C and TBAF (17 .0 mL, 17.03 mmol.) After 2 h at RT, the reaction is complete and the reaction is quenched with MNACI and extracted with EOASc.

The product is purified with the help of KFC when eluting with a mixture of 50:50 heptane:E1(OAc) and tert-butyl ether 4-(11-(5-(1-hydroxymethylcyclopropyl)-isoxazol-3-ylcarbamoyl|-1H-indol-5- yloxy)-5,7-dihydropyrrolo|3,4-4|Ipyrimidine-b6-carboxylic acid, which is then dissolved in DCM (10 ml) and added

TFC (10 ml). The reaction mixture is stirred for 20 minutes. Then the organic substances are evaporated and the crude product is transferred to EtOAc and MNAOH (37 95 in water), added to the free base of the amine.

The flask is then pumped again to remove excess EOAc. Then the crude product is introduced into a column with silica gel and eluted with a mixture of DHM:Meon:-MNAOnH from 100:0:0 to 90:9.5:0.5 and the desired compound is obtained. MS (ER) t/2 433.9 (M--1). "H NMR (400 MHz, DMSO-av) b freq./million 11.25 (5, 1 H), 8.65 (a, 9-2.02 Hz, 1 H), 8.31 (j, U -8.84 Hz, 1 H), 8.18 (y, 9U-3.79 Hz, 1 H), 7.50 (a, 9U-2.53 Hz, 1 H), 7.18 (ad, 9U-9.09, 2.27 Hz, 1 N), 6.80 - 6.82 (t, 2 N), 4.99 (in, 1 N), 4.58-4.67 (t, 4 H), 3.66 (y, U-5.81 Hz, 2

N),. 1.10-1.11 (t, 2 N), 1.03 - 1.04 (t, 2 N).

Example 143 143-А. 15-(1-Aminomethylcyclopropyl)-isoxazol-3-yl|1-amide 5-(6,7-dihydro-5H-pyrrolo|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

MH,

M (c);

Sh. Z

! If; ke

To Kh-m

N o nn

To a solution of tert-butyl ether 4-11-(5-(1-hydroxymethylcyclopropyl)-isoxazol-3-ylcarbamoyl|-1H-indol-5-yloxy)-5,7-dihydropyrrolo|3,4-4|pyrimidine-b -carboxylic acid (500 mg, 0.939 mmol) in THF (10 ml), triethylamine (0.262 ml, 1.88 mmol), methanesulfonyl chloride (0.110 ml, 1.41 mmol) and DMAP (11.5 mg , 0.094 mmol).After 2 h, the reaction is complete and the reaction is quenched with water and the organics are extracted with EtOAc. The crude product after concentration is dissolved in THF (30 mL) and Mn in MeonH (1.82 mL, 12.8 mmol) is added. The reaction mixture is stirred for 36 h. Then volatile substances are removed and the crude product is dissolved in

DCM (10 mL) and then TFA (10 mL, 130 mmol) was added. In 10 minutes. volatile substances are removed under vacuum. The product is dissolved in EtOAc and then MNAOH is added. Organic substances are separated and the crude product is purified by means of KFC, eluting with a mixture of DCM:Meon:mMn.sn (from 100:0:0 to 92:7:1) and the desired compound is obtained. MS (IER) t/h 432.0 (M--1). "H NMR (400 MHz, DMSO-dv) b freq./million 8.55 (5, 1 H), 8.35 (y, 9U-8.84 Gu, 1 H), 8.15 (a, 9U -3.54 Hz, 1 N), 7.44 (a, 0-2.53 Hz, 1 N), 7.11 (aa, U-9.09, 2.53 Hz, 1 N), 6, 77 (5, 1 N), 6.70 (a, 9U-4.04 Hz, 1 N), 4.09 (a, 2-11.87 Hz, 4 N), 2.94 (5.2

H), 1.05 (a, 9-3.03 Gu, 4 H).

Example 144 144-А. 4-(1-(5-(1-formylcyclopropyl)-isoxazole-3-ylcarbamoyl|-1H-indol-5-yloxy)-5,7-dihydropyrroloY3,4-4|pyrimidine-b-carboxylic acid tert-butyl ether acid. o (c)

M

ХХ IF; yo

M. 22 M di

Where is it?

Triethylamine (1.086 ml, 7.19 mmol) and DMSO (1.11 ml, 15.6 mmol), tert-butyl ether 4- 1-I(5-(1- hydroxymethylcyclopropyl)-isoxazol-3Z-ylcarbamoyl|-1H-indol-5-yloxy)-5, 7-dihydropyrroloyl3,4-4-pyrimidine-6-carboxylic acid (0.83 g, 1.559 mmol) in DCM (5 ml) and DMSO (1 ml). The reaction mixture was stirred at 0 "C for 2 h. After the end of the reaction, it is stopped with MNASI, extracted and evaporated. Then tert-butyl ether 4-11-(5-(1-formylcyclopropyl)-isoxazol-3-ylcarbamoyl|-1H-indol-5-yloxy)-5,7-dihydropyrrolo|3,4-4|Ipyrimidine-b6 -carboxylic acid is isolated with the help of KFC when eluting with a mixture from 100:0 heptane:'E(Ac to 0:100 heptane'E(UAc. MS (IER) t/2 531.0 (M-H1). 144-B. 15-(1-Dimethylaminomethylcyclopropyl)-isoxazol-3-yl|I-amide 5-(6,7-dihydro-5H-pyrrolo|3,4-

Phipyrimidin-4-yloxy)-indole-1-carboxylic acid.

H o M--

Х Со Ж со

MO 2 M Sv

To Kh-m

N o nn

To a solution of tert-butyl ether 4-11-(5-(1-formylcyclopropyl)-isoxazol-3-ylcarbamoyl|-1H-indol-5-yloxy)-5, 7-dihydropyrrolo|3,4-4|pyrimidine- of b6-carboxylic acid (120 mg, 0.226 mmol) in DHE (2 mL) add dimethylamine (0.34 mL, 0.679 mmol) and sodium triacetoxyborohydride (192 mg, 0.905 mmol). After 2 hours the reaction ends, saline solution is added and the product is extracted with EAs. The organic matter is dried and evaporated to obtain a crude product.

The mixture was diluted with DCM (10 mL) and then TFA (10 mL, 130 mmol) was added. After 10 minutes, volatile substances are removed under vacuum. The product is dissolved in EIOAc and then MNAOH is added.

The organic substances are separated and the crude product is purified with the help of KFC when eluting with a mixture of dhm:meon:Mnan (from 100:0:0 to 92:7:1) and I5-(1-dimethylaminomethylcyclopropyl)-isoxazole-3-yl|-amide is obtained 5-(6,7-dihydro-5H-pyrrolo!|3,4-4|pyrimidin-4-yloxy)-indole-1-carboxylic acid. MS (IER) t/ 460.9 (M--1). "H NMR (400 MHz, DMSO-av) b frequency/million 8.55 (5, 1 H), 8.29 (j, 9U-8.84 Hz, 1 H), 8.16 (a, 9 -3.79 Gu, 1 H), 7.47 (a, 9-2.27 Hz, 1 H), 7.16 (5, 1 H), 6.82 (5, 1 H), 6.75 (y, 9-4.04 Hu, 1 N), 4.06-4.15 (t, 1 N), 2.57 (5.2 N), 2.20 (5.6 N), 1, 17 (94, 95-227 Hz, 2 N), 0.93 (9, 9-2,27 Hz, 2 N).

The following compounds are obtained by a similar method. 144-6. 15-(1-Methylaminomethylcyclopropyl)-isoxazole-3-yl|-amide of 5-(6,7-dihydro-5H-pyrroloyl3,4-a|pyrimidin-4-yloxy)-indole-1-carboxylic acid.

in

MN

Mo zh her A,

Mi 2 M «di oh-ya

N o nn

MS (IER) t/2 446.1 (M--1). "H NMR (400 MHz, DMSO-dv) 6 ppm 8.55 (5, 1 H), 8.32 (y, 9-9.09 Hz, 1 H), 8.16 (a, 9 -3.79 Hz, 1 N), 7.46 (a, 9-2.53 Hz, 1 N), 7.13-7.14 (t, 1 N), 6.78 (5, 1 N) , 6.7Z (y, 9-3.79 Hz, 1 N), 4.08-4.10 (t, 4 N), 2.84 (5, 2 N), 2.33 (5, Z N ), 1.05-1.18 (t, 2 H), 1.00 - 1.01 (t, 2 H). 144-0. (5-1-(2-Methoxyethylamino)-methyl|-cyclopropyl) -isoxazole-3-yl-amide / 5-(6,7-dihydro-5H-pyrrolo|3,4-4|Ipyrimidin-4-yloxy)-indole-1-carboxylic acid.

N

M

Mao Zedong

SSO and 079

M. 22 M - Kh

M Hmm

N o nn

MS (IER) t/h 490.0 (M--1). "H NMR (400 MHz, DMSO-av) b freq./million 8.55 (5, 1 H), 8.30 (a, 9-9.09 Hz, 1 H), 8.16 (a, 2 -3.79 Hz, 1 H), 7.46 (a, 9-2.27 Hz, 1 H), 7.13 - 7.16 (t, 1 H), 6.75 (a, 9-3 .79 Hz, 1 N), 6.78 (5.1 N), 4.10 (a, 9U-15.16 Hz, 4 N), 3.37 - 3.39 (t, 2 N), 3 .25 (5, Z H), 2.88 (5.2 H), 2.70-2.72 (t, 2 H), 1.07 -1.10 (t, 2 H), 0.98 - 1.00 (t, 2 N).

Example 145 145-А. |5-(1-Methylcyclopropyl)-isoxazol-3-yl|1-amide 5-(6-(2-methylamino-ethyl)-pyrimidin-4-yloxy|- indole-1-carboxylic acid.

M. 22 M PI ed

M o nn

And MN

It is obtained by a method similar to that described in example 73-0. MS (IER) t/: 432.2 (M--1). "N

NMR (400 MHz, DMSO-dv) 5 ppm 8.64 (y, 9-1.01 Hz, 1 H), 8.36 (y, 9-8.84 Hz, 1 H), 8, 15 (a, 9-3.79

Gu, 1 N), 7.43 (a, U-2.53 Hz, 1 N), 7.09 - 7.11 (t, 1 N), 6.97 (5, 1 N), 6.66 (5, 1 N), 6.71 (a, 9U-3.79 Hz, 1 N), 2.84 - 2.89 (t, 4 N), 2.32 (5.3 N), 1, 45 (5.3 N), 1.13-1.15 (t, 2 N), 0.90 - 0.92 (t, 2 N).

The following compounds are obtained by a similar method. 145-8. (5-Isopropyl-1H-pyrazol-3-yl)-amide 5-(6--2-dimethylaminoethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid. (6)

There is Z

! MN

M. 2 M what

M o nn

YAM

MS (ER) t/2 434.2 (Ma-1). "H NMR (400 MHz, DMSO-dbv) b freq./million 12.24 (5.1 N), 10.61 (5.1 N), 8.63 (9.9-1.01 Hz, 1 H), 8.31 (4, U-8.84 Hz, 1 H), 8.18 (a, U-3.79 Hz, 1 H), 7.44 (a, 9-227 Hz, 1 H ), 7.10 (ad, 9U-8.84, 2.53 Hz, 1 H), 7.02 (5, 1 H), 6.71 (a, 9-3.54 Gu, 1 H), 6.34 (a, 9U-1.26 Hz, 1 N), 2.90-3.01 (t, 1

H), 2.84 (Y, 9-7.07 Hz, 2 H), 2.60-2.70 (t, 2 H), 2.19 (5.6 H) 1.25 (a, 9 -7.07 Hz, 6 N). 145-6. (5-Isopropyl-1H-pyrazol-3-yl)-amide /5-16-(2-methylaminoethyl)-pyrimidin-4-yloxy|-indole-1-carboxylic acid

M., 0 day a

MN

Mo M shchi gly y o nn

Academy of Sciences

MS (ER) t/ 420.1 (M'-1). "H NMR (400 MHz, DMSO-dv) 5 ppm 12.24 (brg. 5., 1 H), 8.63 (y, U-1.26

Hu, 1 H), 8.31 (a, U-9.09 Hu, 1 H), 8.18 (a, 9-3.79 Hu, 1 H), 7.43 (a, 9-2, 27 Hz, 1 N), 7.10 (aa, O-8.97, 2.40

Hz, 1 N), 6.97 (a, 9-1.01 Hz, 1 N), 6.71 (a, 9-3.03 Gu, 1 N), 6.34 (5, 1 N), 2.89-3.01 (t, 1 H), 2.76-2.86 (t, 4

H), 2.28 (5, C H), 1.25 (a, 2-7.07 Gu, 6 H).

Example 146 146-А. (5-(1-Trifluoromethylcyclopropyl)-isoxazol-3-yl|-amide 5-16-Kacetylmethylamino)-methyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid.

IS

And these U o

M- what / zo) h oi

Obtained by a method similar to that described in example 21. MS (IER) t/: 515.2 (MAT). "H NMR (400 MHz, DMSO-av) b freq./million 11.44 (5, 1 N), 8.59-8.74 (t, 1 N), 8.30 (a, 9-9, 09 Hz, 1 N), 8.17 (a, 9-3.79 Hz, 1 N), 7.43-7.53 (t, 1 N), 7.10-7.21 (t, 1 N ), 7.04 (5, 1 N), 6.92 (5, 1 N), 6.78 (y, 9-3.54 Hz, 1 N), 4.63 (5, 1 N), 4 .54 (5, 1 N), 3.09 (5, 2 N), 2.84 (5,1 N), 2.10 (5, 2 N), 2.03 (in, 1 N), 1 .48-1.65 (t, 4 H). 146-8. (5-Isopropylisoxazol-3-yl)-amide. 5-16-Kacetylmethylamino)-methyl|-pyrimidin-4-yloxy)-indol-1- of carboxylic acid

MS (ER) t/2 449.19 (M'-1). "H NMR (400 MHz, DMSO-av) 6 parts per million 11.27 (5.1 N), 8.60-8.78 (t, 1

H), 8.27-8.35 (t, 1 H), 8.14-8.21 (t, 1 H), 7.44-7.51 (t, 1 H), 7.14 (aa , U-8.84, 2.53 Hz, 1 H), 6.90-6.97 (t, 1), 6.77 (Her, 922.91 Gu, 1 H), 4.59-4, 61 (t, 1 H), 4.63 (5, 1 H), 4.54 (5, 1 H), 3.10-3.15 (t, 1 H), 3.09 (5.2

H), 2.84 (5.1 H), 2.10 (5, 2 H), 2.03 (5, 1 H), 1.26-1.33 (t, 6 H). 146-C0. (5-Isopropyl-1H-pyrazol-3-yl)y-amide 5-(6-(2-(acetylmethylamino)-ethyl|-pyrimidin-4-yloxy)-indole-1-carboxylic acid nito

Me ran (c)

M yach zobi h o

MS (ER) t/2 462.1 (Ma-1). "H NMR (400 MHz, DMSO-dbv) b freq./million 12.22 (5.1 N), 10.58 (5.1 N), 8.67 (ad, 9U-14.91, 1, 01 Hz, 1 H), 8.32 (y, 2U-8.84 Hu, 1 H), 8.18 (y, 2-3.54 Hu, 1 H), 7.43 (a, 2U-2 .02 Hz, 1 H), 7.03-7.16 (t, 1 H), 6.96 (5, 1 H), 6.72 (0.9U-3.54 Gu, 1 H), 6 .34 (5, 1 H), 3.57-3.69 (t, 2 H), 2.93-3.01 (t, 2

H), 2.93 (5, 2 H-rotary isomer) 2.83-2.89 (t, 1 H), 2.78 (5, 1 H-rotary isomer) 1.93 (a, U-7 ,33 Gu,

With H) 1.25 (9, 2-7.07 Hz, 6 H).

Example 147

I5-(1-Methylcyclopropyl)-isoxazol-3-yl|-amide of 5-I6-(2-methoxyethoxymethyl)-pyrimidin-4-yloxy|- indole-1-carboxylic acid (c), M (6) (6)

I would

UC dya x CHI (6) M

It is obtained by a method similar to that described in example 20-A. MS (IER) t/2 464.0 (M--1). "NN

NMR (400 MHz, DMSO-av) b frequency/million 11.25 (5, 1 N), 8.68 (a, 9U-1.01 Hz, 1 N), 8.31 (a, 9-9 .09 Hz, 1 H), 8.18 (a, 9-3.79 Gu, 1 H), 7.49 (a, 9-2.53 Hz, 1 H), 7.16 (da, 9U- 8.97, 2.40 Hz, 1 N), 7.00 (a, 9-1.01 Hz, 1 N), 6.77 (a, 9-3.79 Gu, 1 N), 6.67 (5, 1 H), 4.57 (5, 2 H), 3.63-3.69 (t, 2 H), 3.46-3.52 (t, 2 H), 3.21 (5 , with H), 1.46 (5, with H), 1.13-1.17 (t, 2 H), 0.90-0.97 (t, 2 H).

Example 148 148-А. 1-tert-butyl ether 2-methyl ether of 4-oxopyrrolidine-1,2-dicarboxylic acid

SU

M

Ho oh ra

Dess-Martin periodinan (12.97 g, 30, 6 mmol).

After the end of the reaction, according to thin-layer chromatography, the reaction is stopped with a saturated solution of ManHsCO3, washed with a saturated solution of sodium thiosulfate and extracted with DCM. The organic substances are dried and evaporated and used in the next stage without purification. 148-8. B-1. 1-tert-butyl ether, 4-ethyl ether, 2-methyl ether of 5-oxopiperidine-1,2,4-tricarboxylic acid and B-2: 1-tert-butyl ether, 5-ethyl ether, 2-methyl ether 4 - oxopiperidine-1,2,5-tricarboxylic acid o..O | oo o) (6) is) M more and what oo 4 d

B-1 in-2

Boron trifluoride etherate ( 2.14 mL, 16.9 mmol), followed by ethyl diazoacetate (2.39 mL, 23.0 mmol). After stirring overnight, the reaction was quenched with water and extracted with EOAc. These two products were isolated (as inseparable mixtures ) with the help of KFC when eluting with heptane:E(Ac 1:1. MS (IER) t/2 328.1 (M-1). 148-С. (53-0-1. 7-Tert-butyl ether, b -ethyl ether of 4-oxo-4,5,6,8-tetrahydro-ZN-pyridoyi3,4-9-pyrimidine-b6,7-dicarboxylic acid and (g)-C-2.b-tert-butyl ether, 7-ethyl Ester of 4-oxo-3,5,7,8-tetrahydro-4H-pyrido|4,3-4|Ipyrimidine-b,7-dicarboxylic acid i; o NM zm -

M. o o mor

Y Y Zhuo

Zhuo ogo "Zh Zh

C-1 c-2

To a solution of 1-tert-butyl ether, 4-ethyl ether, 2-methyl ether of 5-oxopiperidine-1,2,4-tricarboxylic acid and 1-tert-butyl ether, 5-ethyl ether, 2-methyl ether of 4-oxopiperidine -1,2,5-tricarboxylic acid (2.84 g, 8.2 mmol) in BEN (20 ml) add formamidine acetate (1.347 g, 12.93 mmol) and sodium ethoxide (6.99 g, 21.6 mmol) ) and the reaction mixture is heated at 90 "C. After 3 hours, 0.75 equiv. of formamidine acetate is added. After the end of the reaction according to LCMS, the reaction mixture is evaporated, the reaction is stopped with MNASI and extracted with DCM. The products are purified with the help of KFC during elution heptane'E(Ac 1:22 and isolated in the form of a mixture that does not separate. MS (IER) t/2 3241 (Ma1) 148-0. (95-0-1. 7-Tert-butyl ether, b-ethyl 4-chloro-5,8-dihydro-6H-pyridoyi3,4-9|pyrimidine-b,7-dicarboxylic acid ether and (g5)-0-2.b-tert-butyl ether, 7-ethyl ether 4-chloro -7,8- dihydro-5H-pyridoyi4,3-4|Ipyrimidine-b, 7-dicarboxylic acid

M. SI Mem

Oh what

M. SI o mor and Y Zhuo

Jo oo x d 0-1 r-2

To a solution of a mixture of 7-tert-butyl ether, b-ethyl ether of 4-oxo-4,5,6,8-tetrahydro-ZH-pyridoY3,4-4|pyrimidine-6,7-dicarboxylic acid and b-tert-butyl ether, 7-ethyl ether 4-oxo-3,5,7,8-tetrahydro-4H-pyrido|4,3-4|Ipyrimidine-b, 7-dicarboxylic acid (1.5 g, 4.64 mmol) in To DHE (25 mL) was added carbon tetrachloride (1.34 mL, 13.9 mmol) and triphenylphosphine (2.43 g, 9.28 mmol).

The reaction mixture is refluxed and after the end of the reaction, according to LCMS, the solvents are removed and the products are isolated by means of KFC, eluting with a mixture of heptane:EIAs 80:20. The two products are then separated. 7-tert-butyl ether, b-ethyl ether of 4-chloro-5,8-dihydro-6bH-pyridoi/3,4-4|pyrimidine-b6, 7-dicarboxylic acid MS (IER) t/2 342.1 ( Ma) and 4-chloro-7,8-dihydro-5H-pyrido|4,3-d|pyrimidine-b6,7-dicarboxylic acid b-tert-butyl ether 7-ethyl ether MS (ER) it/7 3421 ( M-41) are allocated almost exactly in the ratio of 4:1. 148-E. 7-tert-butyl ether, b6-ethyl ether (x)-4-(1H-indol-5-yloxy)-5,8-dihydro-6H-pyridoyl3,4-a|pyrimidine-b, 7-dicarboxylic acid

M.O

SSO

M. 22 M o Nn

IN

Joe

WHAT?

To a solution of 7-tert-butyl ether, b-ethyl ether of 4-chloro-5,8-dihydro-6H-pyridoyl3,4-a|pyrimidine-b,7-dicarboxylic acid (1 g, 2.93 mmol) in CH3SM (30 mL) add 5-hydroxyindole (0.779 g, 5.85 mmol) and DBU (0.88 mL, 5.85 mmol). After heating at 60 "C for 5 hours, the reaction mixture is evaporated and the product is purified using KFC, eluting with a 1:1 mixture of heptane-HEUAs. MS (IR) t/: 439.1 (M--1). 148-PE. 7-tert-butyl ether, b-ethyl ether (zht)-4-11-(5-cyclopropyl-isoxazol-3-ylcarbamoyl)-1H-indol-5-yloxy|-5,8-dihydro-6bH-pyridoyl3, 4-4|pyrimidine-b,7-dicarboxylic acid fe)va,

M. 2 M

N o H-M em c) M ran;

It is obtained by a method similar to that described in example 56-A. MS (IER) t/72 589.1 (Ma-1) 148-0. (5)-Methylamide 4-11-(5-cyclopropylisoxazol-3Z-ylcarbamoyl)-1H-indol-5-yloxy|-5,6,7,8-tetrahydropyrido|3,4-4|pyrimidine-b6-carbon Fe acids)

LI Z

M. 22 M um

M

/th o M. (6)

To a solution of 7-tert-butyl ether, b-ethyl ether 4-11-(5-cyclopropylisoxazol-3-ylcarbamoyl)-1H-indol-5-yloxy|-5,8-dihydro-6H-pyrido/3,4- 4|pyrimidine-b,7-dicarboxylic acid (110 mg, 0.196 mmol) in a mixture of THF/EuOH/H2O (3:11 ml) was added HyION (0.016 g, 0.392 mmol) and the reaction mixture was stirred until the starting material was exhausted. Then the reaction is stopped with 1 n.

HCl (2 ml) and extracted with EAs. After drying and evaporation, the crude product is dissolved in DCM (3 ml) at 0 "С, oxalyl chloride (0.026 ml, 0.294 mmol) and DMF (2 drops) are added.

Methylamine (2 M in THF) (0.49 mL, 0.981 mmol) was then added and the reaction mixture was stirred for 1 h. at CT. After treatment with water and extraction with EA, the crude product was dissolved in DCM (2 mL) and TFA (1 mL) was added. After removal of the solvent in vacuo and alkalinization using MNAOH, the product is purified using KFC when eluting with a mixture

DHM:Meon:MNn.On from 100:0:0 to 90:8:2. MS (ER) t/2 474.1 (M--1). "H NMR (400 MHz, DMSO-av) b freq./million 11.21 (5.1 N), 8.43 (5.1 N), 8.21-8.33 (t, 1 N), 8.15 (а, 9-3.79 Hz, 1 H), 7.94 (y, У-5.81 Hz, 1 H), 7.44 (а, ю9-2.27 Hz, 1 H) , 7.12 (a, 2-9.09 Hz, 1 N), 6.75 (a, 9-3.03 Hz, 1 N), 6.65 (5, 1 N), 3.91-4 .15 (t, 2 H), 3.61 (Bg. 5, 1 H), 2.83-2.95 (t, 2 H), 2.66 (a, 9U-4.80 Hz, Z H ), 2.12-2.24 (t, 1 N), 1.03-1.17 (t, 2 N), 0.94 (ad, U-4.80, 2.53 Hz, 2 N) .

Example 149 149-А. (4-(1H-Indol-5-yloxy)pyridin-2-yl)methanol

M

XX

(oh; t but still

M

1H-indol-5-ol (534 mg, 4.01 mmol) and cesium carbonate (1307 mg, 4.01 mmol). The reaction vessel is hermetically closed and heated at 160 °C with microwave radiation for 30 minutes. Then the reaction mixture is cooled to room temperature and diluted with saline solution and with DCM. The resulting layers are separated and the aqueous layer is extracted three more times with

DXM. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated.

The resulting residue is purified using KFC (0-100 90 EtOAc/heptane) and the desired compound is obtained. MS (IER) t/: 241.2 (M'-1). 149-V. Tert-butyl-(4-(1H-indol-5-yloxy)pyridin-2-ylmethyl(methyl)carbamate

N

M

DU

(c) va (o) M - gr (c)

To a solution of (4-(1H-indol-5-yloxy)pyridin-2-yl)methanol (2 g, 8.32 mmol) in THF (40 mL) was added triethylamine (3.48 mL, 24.97 mmol). The reaction mixture was cooled to 0 °C and methanesulfonyl chloride (0.973 mL, 12.49 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 45 min. and then the reaction mixture is warmed to room temperature and a 40% solution of methylamine in water (7.21 mL, 83 mmol) is added. The reaction mixture is stirred for 30 minutes. and then diluted with saline solution. The resulting mixture is extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was then dissolved in DCM (50 mL) and di-tert-butyl dicarbonate (2.0 g, 9.15 mmol) was added.

The reaction mixture is stirred for about 30 minutes. at room temperature and then it is diluted with a saturated aqueous solution of MansoOz. The resulting mixture is extracted twice using

DXM. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated.

The resulting residue is purified using KFC (0-100 90 EtOAc/heptane) and the desired compound is obtained. MS (IER) t/2 354.3 (M--1). 149-6. Tert-butyl-(4-(1-(5-cyclopropyl-1-methyl-1H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy)pyridin-2-ylmethyl(imithyl)ucarbamate

IN

M

M what Z t u, (c) a ze M - a; (at)

Phenyl-5-cyclopropyl- 1-Methyl-1H-pyrazole-3-ylcarbamate (126 mg, 0.488 mmol) prepared as described in Example 5-M. The resulting mixture is heated to 0 "C and sodium hydride (60 95 dispersion in oil; 39.0 mg, 0.98 mmol) is added. The reaction mixture is stirred at 0 C for 30 min. and then the reaction is stopped with a saturated aqueous solution of MNACI. The resulting mixture diluted with brine and DCM. The resulting layers were separated and the aqueous layer was extracted twice with DCM. The organic layers were combined, dried over anhydrous Mag5O»4, filtered, and concentrated. The resulting residue was purified by KFC (0-100 95 EuSO4Ac/heptane) and obtain the desired compound. MS (ER) t/2 517.6 (M--1). 149-0. M-(5-Cyclopropyl-1-methyl-1H-pyrazol-3-yl)-5-( 2-(methylamino)-methyl)pyridin-4-yloxy)-1H-indole-1-carboxamido n

M

U-M

M t Zh

SHO udo, (o) yuYu

NM -

M

To a solution of tert-butyl-(4-(1-(5-cyclopropyl-1-methyl-1H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy)pyridin-2-yl)umethyl(methyl)carbamate (0.124 g, 0.240 mmol) in DCM (5 ml) add TFA (2 ml, 0.240 mmol). The reaction mixture is stirred for about 30 minutes. and then concentrated in vacuo to almost dryness. The residue is dissolved in DCM, diluted with water and neutralized by adding a saturated aqueous Mansaoz solution. The resulting layers are then separated and the aqueous layer is extracted twice with DCM. The organic layers were combined, dried over anhydrous NaCl, filtered and concentrated. The resulting residue is purified using KFC (0-15 u6o MEON/DXM)

and get the desired compound. MS (IER) t/ 417.2 (M--1). "H NMR (400 MHz, DMSO-av) 6 ppm 0.64-0.70 (t, 2 H), 0.96-1.02 (t, 2 H), 1.87-1, 96 (t, 1 H), 2.27 (v, C H), 3.71 (5, 2 H), 3.80 (5, C H), 6.16 (y, 90.51 Hz, 1 H), 6.73 (ai, 9U-3.79, 0.51 Hz, 1 H), 6.80 (da, 9U-5.56, 2.53 Hz, 1 H), 6.93 (y , 9U-2.02 Hz, 1 H), 7.09 (yes, 9U-8.97, 2.40 Hz, 1 H), 7.42 (a, 952.27 Hz, 1 H), 8, 17 (y, 9-3.54 Hz, 1 H), 8.33 (a, 9U-8.84 Hz, 1 H), 8.36 (a, 9-5.81 Hz, 1 H).

The following compounds are obtained by a similar method.

With stkoannneyutyu | 0 nyaeayumo 1 about N -th

Kk -k (DMSO-45 with the addition of "1 95 a-TFC) and Mn (6 parts/million 0.73-0.83 (t, 2 N), 0.92- o; 1.07 (t, 2 H), 1.88-2.02 (t, 1 H), 2.61 o (5, C H), 4.931 (5.2 H), 6.21 (5.1 H), 6.78 149-E (a, 9U-3.03 Hz, 1 H), 7.16 (aa, 9-8.97, 403.3

N | and 2.40 Hz, 1 N), 7.20-7.27 (t, 2 N), 7.50 r sh- (a, 9-2.53 Hz, 1 N), 8.18 (a, 9-3.79 Hz,

M-(5-cyclopropyl-1H-pyrazol-3-yl)-5-(thi t (9, 379.09 Hz, 1 NU, 8.5878.75 (2-(methylamino)methyl)pyridin-4- And yloxy)-1H-indole-1-carboxamide o n

M y -- | (DMSO-ov) b parts/million 2.26 (5, Z H), / 3.70 (v, 2 H), 3.94 (v, Z H), 6.75 (j, iv) E 93.79 Hz, 1 N), 6.79 (ai, 9-5.56, 2.53

EE HC, 1 H), 6.92 (y, 9-2.27 Hz, 1 H), 7.06 149-E Sho (v, 1 NU, 7.11 (49, 94-8.84.2 ,53 Hz, ),I 0792

NM sh- 7.42 (a, 9-2.27 Hz, 1 H), 8.18 (a, 9-3.79

M-(1-methyl-5-(trifluoro-methyl)-1 H- (io sa Hz, Hz peaks, 1 HO, 8.35 pyrazol-3-yl)-5-(2-I'' (methylamino) methyl)pyridin-4-yloxy)-1H-indole-1-carboxamide o H

M udkak

MK b 0 | (dmso-dv) b freq./million 1.34 (5, 9 H), and 2.29 (v, 3 H), 3.74 (5, 2 H), 6.67 (5, 1 H) , o 6.74 (9, 9-3.3 Hz, 1 H), 6.81 (aa, 9U-5.7, 149-С: 2.4 Hz, 1 H), 6.94 (a, 9-23 Hz, 1 N), 420.2 i 7.10 (aa, 9U-9.0, 2.4 Hz, 1 N), 7.42 (y,

NM sh- y-2.5 Hz, 1 N), 8.17 (y, 9-3.5 Hz, 1 N),

M-(5-tert-butylisoxazol-3-yl)-5-(2-8,33-8,39 (t, 2 M) (methylamino)methyl)-pyridin-4-yloxy)-1H-indol-1 -carboxamide o n

Uh

M -k (DMSO-av) 6 ppm 0.88-0.98 (t, 2 x yuyu H), 1.03-1.13 (t, 2 H), 2.11-2.22 (t, p; 98.53, 8.53, 5.05, 4.93 Hz, 1 H), 2.30 o (5, C H), 3.75 (5.2 H), 6.65 (5, 1 H), 6.75 149-H (a, 9-3.54 Hz, 1 H), 6.82 (yes, 9U-5.56, 404.2 and 2.53 Hz, 1 H ), 6.94 (y, 9-2.53 Hz, 1 N),

NM sh- 7.11 (aa, 0-8.97, 2.40 Hz, 1 H), 7.43 (y,

M-(5-cyclopropylisoxazol-3-yl)-5-(2-BZ (t and 58.79 g, ((methylamino)-methyl)pyridin-4-iso 11 yloxy)-1H-indole-1-carboxamide

Example 150 150-A. (4-(1H-Indol-5-yloxy)pyrimidin-2-yl)methylacetate

N

M udo; (is)

WITH

AJ Fr

M with (c)

To the suspension of metallic zinc nanopowder (5iget SPeptisai5; average particle size 75-125

Nm) (1.34 g, 20.52 mmol) in DMF (8 mL) was added 1,2-dibromoethane (0.19 mL, 2.2 mmol). The heterogeneous mixture is heated at 60 "C and then stirred for 10 minutes. The mixture is cooled to room temperature and chlorotrimethylsilane (0.24 ml, 1.8 mmol) is added to it. Then the reaction vessel is sonicated in a water bath for 30 minutes at room temperature. The suspension was then allowed to settle for about 30 min to allow the solid to settle, and then the supernatant was removed with a syringe. DMF (8 mL) was then added, followed by bromomethyl acetate (1.00 mL, 10.3 mmol). Then the reaction mixture stirred for 2 h at room temperature. The suspension was then allowed to stand for 1 h to allow the solid to settle. Then, in a separate flask, 5-(2-chloropyrimidin-4-yloxy)-1H-indole (450 mg, 1.83 mmol), obtained as described in Example 73-A, then DMF (3 mL) is added to 5-(2-chloropyrimidin-4-yloxy)-yl!H-indole, then

Ra(arr)Si»CHnosSi» (230 mg, 0.28 mmol). To this solution, a portion of the supernatant liquid (E ml) taken from a flask containing an organozinc compound is added with a syringe. The reaction mixture is heated at 50 "C for 16 hours, then cooled to room temperature and diluted with DCM and a saturated aqueous solution of MNASI. The layers are separated and the aqueous layer is extracted 2 more times with DCM. The organic layers are combined, dried over anhydrous Ma»25O», filtered and concentrated. The obtained residue was purified by means of KFC (0-60 96 EtOAc/DHM) and the desired compound was obtained. MS (IR) t/2 284.0 (M--1). 150-8 (4-(1H-Indol-5-yloxy)pyrimidin-2-yl)methanol

M uv, (c)

WITH

AC of the United Nations

M

To a solution of (4-(1H-indol-5-yloxy)pyrimidin-2-ylmethylacetate (0.51 g, 1.8 mmol) in Men (18 ml) at 0 "C is added solid KgSO3 (0.6 g, 4 .5 mmol). The reaction mixture is stirred for 30 min. at 0 "C and then warmed to room temperature and stirred for another 30 min. Then the reaction mixture is diluted with DCM and water and the layers are separated. The aqueous layer is extracted 2 more times with DCM. The organic layers are combined, dried over anhydrous Ma5bOx, filtered and concentrated to give the desired compound. MS (IR) t/2 242 1 (M--1). 150-C. Tert-butyl-(4-(1H) -indol-5-yloxy)pyrimidin-2-yl)umethyl (methyl)-carbamate

N uv, (o)

SI ie

AND

To a solution of (4-(1H-indol-5-yloxy)pyrimidin-2-yl)methanol (0.47 g, 1.95 mmol) and triethylamine (0.815 ml, 5.84 mmol) in THF at 0 "C is added methanesulfonyl chloride (0.228 mL, 2.92 mmol).

The reaction mixture was stirred at 0 °C for 45 min. and then 40 95% of a solution of methylamine in water (3.37 mL, 39.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was then diluted with brine. and ethyl acetate. The layers are separated and the aqueous layer is extracted 2 more times with ethyl acetate. The organic layers are combined, dried over anhydrous Mag5O.:, filtered and concentrated. The resulting residue is then diluted with DCM (15 mL), and di-tert is added to the resulting solution -butyl dicarbonate (0.42 g, 1.9 mmol).

The reaction mixture is stirred for about 30 minutes. at room temperature and then it is diluted with a saturated aqueous solution of MansoOz. The resulting mixture is extracted twice using

DXM. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated.

The obtained residue is purified with the help of KFC (30-80 95 EUAc(2.5 96EUN)/heptane) and the desired compound is obtained. MS (IER) t/2 355.2 (M--1). 150-0. Tert-butyl-(4-(1-(5-cyclopropyl-1-ethyl-1H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy)pyrimidin-2-yl)umethyl(methyl)carbamate in - du /Y (in) s and r

Phenyl-5-cyclopropyl- 1-Ethyl-1H-pyrazole-3-ylcarbamate (29.5 mg, 0.109 mmol), which was prepared as described in Example 5-5. The temperature of the mixture is set at 0 °C, and then Man (60 95 dispersion in oil; 11.85 mg, 0.296 mmol) is added, and then the reaction mixture is stirred for 30 minutes. Then the reaction is stopped with a mixture of 10 95 ASON/Meon (0.3 ml) and further diluted with DCM and a saturated aqueous solution of ManHsS3. The resulting layers are then separated and the aqueous layer is extracted 2 more times with DCM. The organic layers are combined, dried over anhydrous Mg5O:, filtered and concentrated. The resulting residue is purified using KFC ( 10-100 95 EIHUAc (2.5 9?6EION)UDHM) and get the desired compound. MS (ER) t/2 532.3 (M-H1). 150-E. M-(5-Cyclopropyl-1-ethyl -1 H-pyrazol-3-yl)-5-(2-(methylamino)methyl)-pyrimidin-4-yloxy)-1 H-indole-1-carboxamide. (o; H y-x -eM

WITH

Her (o) s

J

M o

To a solution of tert-butyl-(4-(1-(5-cyclopropyl-1-ethyl-1H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy)pyrimidin-2-yl)umethyl (methyl)carbamate (33 mg, 0.062 mmol) in DCM (2 ml) at 0 "C is added TFA (0.7 ml, 9.1 mmol). The reaction mixture is stirred for 30 min. at 0 "C and then kept at room temperature for another 20 minutes. The reaction mixture is then concentrated in vacuo to almost dryness and then diluted with DCM and water. The mixture is neutralized by adding a saturated aqueous solution of ManHCO3 and the resulting layers are separated. The aqueous layer is extracted 2 more times with DCM. The organic layers were combined, dried over anhydrous NaCl, filtered and concentrated. The obtained residue is purified using KFC (0-20 96 meonudhm) and the desired compound is obtained. MS (IER) t/2 432.2 (M--1). (DMSO-ав) b freq./million 0.62-0.71 (t, 2 H), 0.93-1.02 (t, 2 H), 1.37 (i, 9-7.20 Gu , with H) 1.86-1.99 (t, 1 H), 2.30 (c, with H), 3.71 (5.2 H), 4.15 (a, 9-7.24

Hz, 2 N), 6.16 (5, 1 N), 6.71 (a, 9U-4.29 Hz, 1 N), 6.87 (y, 9-5.56 Hz, 1 N), 7.12 (yes, 9-9.09, 2.27 Hz, 1 H), 7.46 (a, 9-2.27 Hz, 1 H), 8.17 (a, 9-3.79 Gu , 1 N), 8.31 (a, 9-9.09 Hz, 1 N), 8.61 (a, 9-5.56 Hz, 1 N), 10.64 (5.1 N).

Example 151: Study of inhibition of the viability of Ba/E3-TeI-KOV cells

This assay is a cell-based assay designed to examine compound-mediated inhibition of Ba/R cell proliferation and viability by assaying luciferase bioluminescence using a commercially available system called SeyyiTieg-

Sio "M. In this case, a specially modified Ba/e3-TeI-KOV cell line is used.

These cells are genetically engineered so that intact signaling through the tyrosine kinase domain of COEC is critical for their viability. Inhibition of signal transmission with the help of KOM leads to cell death, which is quantitatively studied using the study of cell viability. It is a homogeneous bioluminescence assay that provides a quick, simple and sensitive determination of the number of viable cells in a culture by generating a luminescence signal whose intensity is proportional to the amount of ATP contained in the cells. A dilution of the compound that inhibits COC is incubated with Ba/E3-TeI-COE cells for 48 hours.

and cell viability characteristics are determined using a suitable luminometer.

This research is carried out with Ba/E3-TeeI-COC cells. Cells are grown at 37"С (5 95 СО") in a medium containing KERMI-1640, 10 96 fetal bovine serum, 2 mM sSishat, 100 U/ml penicillin/streptomycin mixture and 0.8 mg/ml 5418. Per day before conducting the experiment, the medium is replaced. On day 1, cells are placed in white solid-bottomed 384-well plates with 5,000 cells/well in 25 μl of culture medium. The dose-response relationship is constructed at 10 points as follows: first, the compounds are serially diluted 3-fold in 10095 DMSO at an initial concentration of 10 mM. Then the compounds are further diluted 166.67 times in the culture medium. µl of the diluted compound is added to the wells of the tablet together with 25 µl of the culture medium.

The final concentrations of the compounds are as follows: 10, 3.33, 1.11, 0.37, 0.123, 0.041, 0.0137, 0.0046, 0.0015 and 0.0005 µM. The final concentration of DMSO is 0.1 95. Wells containing no cells and wells containing 0.1 96 DMSO are controls. On day C, the lyophilized SePpeg-Sio buffer and substrate and cell plates are first equilibrated at room temperature. The substrate is reconstituted in buffer and 30 μl of the reconstituted substrate is added to each well. After incubation for 10 min. at room temperature, the tablets are read using a luminometer. Compounds are tested to obtain 10 dose-response values and each concentration is tested three times in a given tablet. Each tablet is examined twice. Data analysis and calculation of ISzo values are carried out with the help of Ekhsei and Rgiz5t software. 11156 8 2 sh 17350... | ...Y.9 g Zh«/« 7 76A | 7778 2

Z33E | 9 57-16 7 765A Sh | 8 777.206 | щЩщ6 7565 ющЩщ | 89 1 LZIAAM | 6 2 111 1972E | 9 lav y111111716 mon shi shin 6856 1 yush8v8

Claims (27)

1. The compound according to the Formula Sh o / A y- in Ag. M y M M x Kk y ? Sh or its pharmaceutically acceptable salt, in which Ki is hydrogen or Si-Svalkyl; Kz is hydrogen or Si-Svalkyl; Co represents hydrogen or halogen; K;7 is hydrogen or Si-Svalkyl; X represents O or 5; Kz is hydrogen or Si-Slalkyl; Co is selected from the group consisting of (SKikKiI2)MKizKia, (SKikKi2)vheterocycle, (SKikKiz)OK5, (SKikKizSO)EkK: z and (SKikKiz)claim 5(O)tKi17; At" is a phenyl, naphthyl, 5- or b-membered monocyclic heteroaryl, where each heteroaryl has I, 2 or 3 ring heteroatoms selected from M, O or 5, and where said phenyl, naphthyl or heteroaryl group is unsubstituted or substituted by by means of I, 2 or 3 groups independently selected from the group consisting of C1-Salkyl, C1-C1haloalkyl, halogen, hydroxyl, CO»C1-Salkyl, phenyl and C3-C1cycloalkyl; t takes the value 0, 1 or 2; n takes the value 1, 2 or 3; E represents the missing member, O or MKi8; Who, who? and Kiv are the same or different and in each case independently selected from the group consisting of hydrogen and Si-Sdlalkilu; and Kis, Ki4, Ki, and Ki7 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl, phenyl, and heterocycle, each of which is substituted with 0, 1, or 2 groups independently selected from hydroxyl groups, amino groups and mono- and di-Ci-Salkylamino groups. 2. The compound according to claim 1, which corresponds to Formula U: 7 o / A 8 Bash 2 M y sy r M x v "z U or its pharmaceutically acceptable salt, in which Co is selected from the group consisting of СНоМКизКии. СНоОКИз, СНС (О ЕК з, (СНо)пе(О)шиМ(К 18)» and СН»З(О КИ»; E represents the missing member, O or MKi8; Kiv represents hydrogen, methyl or ethyl; and Kis, Ki4 , Ki and Ki7 are each independently selected from the group consisting of hydrogen, C1-Slalkyl, and hydroxyC1-Slalkyl. 3. Compound zap. 1, in which Kz is hydrogen; and Ko is selected from the group consisting of (СНо)иМНКИі»z, (СКікКі?2)pheterocycle, (СКікКі2)вOK 5, (СНо)ве(О)ткКі17 and (СНо)ве(О) тім (Кв) 2 ; n takes the value 1 or 2; C is hydrogen, C1-C1 alkyl, hydroxyC1-C1 alkyl or C3-C6 cycloalkyl; Kiz is hydrogen or Si-Slalkyl; Ki is Si-Slalkill; and Kiv is independently selected, in each case, from the group consisting of hydrogen, methyl, or ethyl. 4. The compound according to claim 1 or its pharmaceutically acceptable salt, in which Ki is hydrogen, methyl or ethyl; Kz is hydrogen; K" represents hydrogen, fluorine or chlorine; X represents O or 5; Kz" is selected from the group consisting of hydrogen and Si-Slalkyl; Co is selected from the group consisting of СНоМКіИзКії, SNоheterocycle, СНоОК»5, ССО ЕКіз and СНОБ(ОКИ»; At» is a phenyl, 5-membered monocyclic heteroaryl, where the heteroaryl has one ring nitrogen atom and 0 or 1 additional ring a heteroatom selected from M, O or 5, and wherein said phenyl or heteroaryl group is unsubstituted or substituted by 1, 2 or 3 groups independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, hydroxyl, CO»Ci-Cialkyl, phenyl, and C3-Cicycloalkyl; t is 0, 1, or 2; E is O or MKii; Kiv is hydrogen or Ci-Cialkyl; and Kis, Ki, Kis, and Ki7 are each independently selected from the group consisting of hydrogen, C1-Salkyl, C3-Swicycloalkyl, phenyl, and heterocycle, each of which is substituted with 0, 1, or 2 groups independently selected from hydroxyl, amino, and mono- and di-C1-Salkylamino. 5. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, in which At" is phenyl, which is optionally substituted by 1 or 2 groups independently selected from halogen, C1-Slalkyl, C1-Slalkoxy, C1-S1haloalkyl and C1 - Halogenalkoxygroups. 6. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, in which At is a 5-membered heteroaryl having one ring nitrogen atom and 0 or 1 additional ring heteroatom selected from M and 0, and where said heteroaryl group is unsubstituted or substituted with 1 or 2 groups independently selected from the group consisting of C 1 -C 1 alkyl, C 1 -C 1 haloalkyl, C 1 -C 1 alkyl oxy, C 1 -C 1 halogen alkoxy, halogen, amino, aminoC 1 -C 1 alkyl, mono- and -di-C 1 -C 1 alkylaminoSi- Clalalkyl, mono- and di-Ci-Clialkylamino group, hydroxyl, CO2Ci-Clialkyl, phenylCi-Clialkyl, C3-SeccycloalkylCo-Soalkyl, aminosulfonyl and mono- and di-Ci-Clialkylaminosulfonyl. 7. The compound according to claim 1 or its pharmaceutically acceptable salt, in which At" represents a group of the formula: Mm--t-4 Katya, in which Co" is selected from the group consisting of C1-C1 alkyl, C3-Seccycloalkyl, C3-C6cycloalkylC1-C1 alkyl, C1-C1 haloalkyl, hydroxyC1-C1 alkyl, phenyl, 5- and b-membered heterocycle, where said heterocycle is a 4- , a 5-, b- or 7-membered monocyclic heterocycle which contains at least one heteroatom selected from O, 5 and M, and which is substituted by 0, 1 or 2 groups independently selected from C1-C1-alkyl, C1-C1-C1-alkyl, halogen, hydroxyl, amino group and mono- and di-Si-Svalkylamino group; and 7 represents 0, MH or M(Ci-Salalkyl). 8. The compound according to claim 7, in which Co" is selected from the group consisting of isopropyl, tert-butyl, cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 1-trifluoromethylcyclopropyl, 1-ethylcyclopropyl, 1-methylcyclobutyl, 1-ethylcyclobutyl, hydroxyl- tert-butyl and trifluoromethyl; and 7. represents 0. 9. The compound according to claim 1, in which K7 is hydrogen. 10. A compound according to the formula BE E ve M Sh Mo o MN p M la X v (c) M or its pharmaceutically acceptable salt. 11. A compound selected from the group consisting of compounds according to the formulas: (c) , or its salt. 12. Compound according to Formula Sh t; in o / 9 u- in Ag. M Y and Kk sh | / 1 M X Kk in 3 Sh or its pharmaceutically acceptable salt, in which Ki is hydrogen or Si-Svalkil; Kz is hydrogen or Si-Svalkyl; Co represents hydrogen or halogen; K;7 is hydrogen or Si-Svalkyl; X represents O or 5; K» 1 Ko, taken in combination, together with the atoms to which they are attached, form a saturated 4-7-membered heterocyclic ring having 1 or 2 ring heteroatoms selected from M, O or 5, where the heterocyclic ring is substituted by 0, 1 or 2 groups independently selected from the group consisting of C1-Salkyl, C1-Shaloalkyl, halogen, hydroxyC1-Salkyl, aminoC1-Salkyl, C3-StycycloalkylC1-Slalkyl, heterocycleC1-Slalkyl, C1-Salkanoyl, mono- and di-C-Salkylaminocarbonyl, C-Salkyloxycarbonyl and C-Salkylsulfonyl; At" is a phenyl, naphthyl, 5- or b-membered monocyclic heteroaryl, where each heteroaryl has 1, 2 or 3 ring heteroatoms selected from M, O or 5, and where said phenyl, naphthyl or heteroaryl group is unsubstituted or substituted by by means of 1, 2 or 3 groups independently selected from the group consisting of C1-Salkyl, C1-Sehalogenalkyl, halogen, hydroxyl, CO»C1-Salkyl, phenyl and C3-Succycloalkyl; t takes the value 0, 1 or 2; n takes the value I, 2, or 3. 13. The compound according to claim 12 or its salt, in which Kv 1 Ko, taken in combination, form a saturated 5- or b-membered heterocyclic ring having one ring nitrogen atom, where the heterocyclic ring is substituted with 0, 1 or 2 groups , independently selected from the group consisting of C1-C1 alkyl, C1-C1 haloalkyl, hydroxyC1-C1 alkyl, aminoC1-C1 alkyl, heterocycleC1-C1 alkyl, C1-C1 alkyl, mono-1 di-C1-C1 alkylaminocarbonyl, mono-1 di-C1-C1 alkylaminocarbonyl -Slalkyl, aminocarbonyls|1-Slalkyl, C-Slalkyloxycarbonyl 1 C-Slalkylsulfonyl. 14. The compound according to claim 12 or its salt, in which Kv 1 Ko, taken in combination, form a saturated 5- or b-membered heterocyclic ring having one ring nitrogen atom in the beta position relative to the pyrimidine ring, where the heterocyclic ring is substituted by by means of 0, 1 or 2 groups independently selected from the group consisting of C1-Slalkyl, C1-Sahaloalkyl, hydroxyC1-Slalkyl, aminoC1-Slalkyl, heterocycleC1-Slalkyl, C1-Slalkanoyl, mono-1 di-C1-Slalkylaminocarbonyl, mono - 1 di-C1-SlalkylaminoC1-Slalkanoyl, mono-1 di-C1-SlalkylaminocarbonylC1-Slalkyl, aminocarbonylC1-Slalkyl, C-Slalkoxycarbonyl, 1 C-Slalkylsulfonyl. 15. The compound according to claim 14 according to the Formula IU Y in Av M KE iv) ts y U- Ag, M | р и и М х пз IM or its pharmaceutically acceptable salt, in which p takes the value 0 or 1; and Kio, Coo, and Coi are independently selected from the group consisting of hydrogen, Si-Slalkyl, hydroxySiIi-Slalkyl, MHC(O)CH" and MNHSNZS(TOCH"). 16. The compound according to claim 14, in which two of the possible radicals Co, Co or Co are hydrogen, and the other is selected from the group consisting of hydrogen, methyl, ethyl or hydroxyethyl. 17. The compound according to claim 12 or its pharmaceutically acceptable salt, in which Ki is hydrogen, methyl or ethyl; Kz is hydrogen; K" represents hydrogen, fluorine or chlorine; X represents O or 5; Kv 1 Co, taken in combination, form a saturated 4-7 membered heterocyclic ring having one ring nitrogen atom, wherein the heterocyclic ring is substituted with 0, 1, or 2 groups independently selected from the group consisting of Si-Svalkyl, C-Svhaloalkyl, halogen, C-Svalcanoyl 1 C-Svalkylsulfonyl; At" is a phenyl, 5-membered monocyclic heteroaryl, where each heteroaryl has one ring nitrogen atom and 0 or 1 additional ring heteroatom selected from M, OO or 5, 1 where said phenyl or heteroaryl group is optionally substituted with 1, 2 or 3 groups, independently selected from the group consisting of C1-Salkyl, C1-Shaloalkyl, halogen, hydroxyl, CO»C1-Salkyl, phenyl and C3-Succycloalkyl; t takes the value 0, 1 or 2. 18. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, in which At" is phenyl, which is optionally substituted by 1 or 2 groups independently selected from halogen, C-Slalkyl, C-Slalkoxy, C-Slahaloalkyl 1 C - Halogenalkoxygroups. 19. The compound according to claim 12 or its pharmaceutically acceptable salt, in which At is a 5-membered heteroaryl having one ring nitrogen atom and 0 or 1 additional ring heteroatom selected from M 1 O, where the specified heteroaryl group is unsubstituted or substituted by means of 1 or 2 groups independently selected from the group consisting of C 1 -C 1 alkyl, C 1 -C 1 haloalkyl, C 1 -C 1 alkyl, C 1 -C 1 haloalkyl, halogen, amino, aminoC 1 -C 1 alkyl, mono-1 di-C 1 -C 1 alkylaminoC 1 -C 1 alkyl, mono-1 di-Ci-Slalkylamino group, hydroxyl, CO2Ci-Slalkyl, phenylCo-Slalkyl, C3-SeccycloalkylCo-Soalkyl, aminosulfonyl and o mono-1 di-Si-Slalkylaminosulfonyl. 20. The compound according to claim 12. or its pharmaceutically acceptable salt, in which At" represents a group of the formula: Mm--t- Katya; in which Co" is selected from the group consisting of C1-C1 alkyl, C3-Seccycloalkyl, C3-S6cycloalkylC1-C1 alkyl, C1-C1 haloalkyl, hydroxyC1-C1 alkyl, phenyl, 5-1 b-membered heterocycle, where said heterocycle is a 4- , 5-, b- or 7-membered monocyclic heterocycle which contains at least one heteroatom selected from 0, 5 1 M, and which is substituted with 0, 1 or 2 groups independently selected from C-Slalkyl, C-Slalkoxy, halogen, hydroxy group, amino group and mono- and di-Si-Svalkylamino group; 1 7, is 0, MH or M(Ci-Salalkyl). 21. The compound according to claim 20, in which Co" is selected from the group consisting of isopropyl, tert-butyl, cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 1-trifluoromethylcyclopropyl, 1-ethylcyclopropyl, 1-methylcyclobutyl, I-ethylcyclobutyl, hydroxyl- tert-butyl and trifluoromethyl; 1 7, is 0. 22. The compound according to claim 12, in which K7 is hydrogen. 23. A compound selected from the group consisting of compounds according to the formulas: And MO n- o y, - o tem M | A ii M o o o u Zh M Mo n- To " FV; s Y sh- o o M AMN I y M A myi m nm - M Ge) 9 5 c) o ushe L M M ly S o KHAN o XX AMN I and NM A NM 2 M and M, or its salt. 24. A pharmaceutical composition containing at least one compound according to any one of claims 1-23 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. 25. A pharmaceutical combination containing a therapeutically effective amount of a compound according to any one of claims 1-23 or a pharmaceutically acceptable salt thereof and one or more additional therapeutically active agents. 26. Use of a compound according to any of claims 1-23 or a pharmaceutically acceptable salt thereof for the manufacture of a medicinal product for inhibiting the activity of MESE-K in a subject, where the use includes administering to the subject a therapeutically effective amount of a compound according to any of claims 1-23 or its pharmaceutically acceptable salt. 27. Use of a compound according to any one of claims 1-23 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disorder or disease mediated by MESE-K in a subject, wherein the use comprises administering to the subject a therapeutically effective amount of the compound for any -any of claims 1-23 or a pharmaceutically acceptable salt thereof, and the disorder or disease is selected from age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa and retinopathy, geographic retinal atrophy.